Compounds for treating certain leukemias

ABSTRACT

Provided herein are compounds, preferably compounds inhibiting tyrosine kinase enzymatic activity of a protein selected from Abelson protein (ABL1), Abelson-related protein (ABL2), or a chimeric protein BCR-ABL1, compositions thereof, and methods of their preparation, and methods of inhibiting tyrosine kinase enzymatic activity of a protein selected from Abelson protein (ABL1), Abelson-related protein (ABL2), or a chimeric protein BCR-ABL1, and methods for treating diseases wherein modulation of BCR-ABL1 activity prevents, inhibits, or ameliorates the pathology and/or symptomology of the disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/733,029, filed Sep. 18, 2018, U.S. Provisional Application No.62/816,637, filed Mar. 11, 2019, and U.S. Provisional Application No.62/889,929, filed Aug. 21, 2019, the disclosures of each of which arehereby incorporated by reference in their entireties for all purposes.

FIELD OF THE INVENTION

Provided herein are compounds, preferably compounds inhibiting tyrosinekinase enzymatic activity of a protein selected from Abelson protein(ABL1), Abelson-related protein (ABL2), or a chimeric protein BCR-ABL1,compositions thereof, and methods of their preparation, and methods ofinhibiting tyrosine kinase enzymatic activity of a protein selected fromAbelson protein (ABL1), Abelson-related protein (ABL2), or a chimericprotein BCR-ABL1, and methods for treating diseases wherein modulationof BCR-ABL1 activity prevents, inhibits, or ameliorates the pathologyand/or symptomology of the disease.

STATE OF THE ART

In chronic myeloid leukemia (CML) the Philadelphia chromosome (Ph),formed by the t(9,22) reciprocal chromosome, translocates in ahaematopoietic stem cell. This chromosome carries the BCR-ABL1 oncogenewhich encodes the chimeric BCR-ABL1 protein. Drugs that inhibit thetyrosine kinase activity of BCR-ABL1 via an ATP competitive mechanism,such as Gleevec®/Glivec® (imatinib), Tasigna® (nilotinib) and Sprycel®(dasatinib), may be effective in treating CML; however, some patientsrelapse due to the emergence of drug-resistant clones. For example,small molecules, or combinations thereof, may be useful to inhibit theactivity of BCR-ABL1 and BCR-ABL1 mutations via the ATP binding site,the myristoyl binding site or a combination of both sites.

SUMMARY

In one aspect, provided herein is a compound of formula (I) or (Ia):

or a tautomer or an N-oxide thereof, or a pharmaceutically acceptablesalt of any of the foregoing, wherein:

-   L is —NH—CO—, —CO—NH—, —NH—SO₂—, or —SO₂—NH—;-   R¹ is optionally substituted C₆—C₁₀ aryl, optionally substituted    5-10 membered heteroaryl, optionally substituted 4-10 membered    heterocycle, C(O)NR⁶R⁷, S(O)₂NR⁶R⁷, NR⁶COR⁷, NR⁶SO₂R⁷, or C(O)OR⁶;-   R² is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₂—C₆ alkenyl, optionally    substituted C₂—C₆ alkynyl, optionally substituted C₆—C₁₀ aryl, or    optionally substituted 5-10 membered heteroaryl;-   R³ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₂—C₆ alkenyl, optionally substituted C₂—C₆ alkynyl, optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl,    optionally substituted aryl, optionally substituted heteroaryl, OR⁶,    or NR⁶R⁷;    or R² and R³ together with the intervening atoms form optionally    substituted C₃—C₈ cycloalkyl or optionally substituted 4-10 membered    heterocycloalkyl;-   R⁴ is optionally substituted C₁—C₆ alkyl, optionally substituted    C₂—C₆ alkenyl, or optionally substituted C₂—C₆ alkynyl;-   X is O or S;-   Y is CH, C—(C₁—C₂ alkyl), or C-halo or N;-   Z is CR⁵ or N;-   R⁵ is H or halogen;-   R⁶ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₆—C₁₀ aryl, or optionally    substituted 5-10 membered heteroaryl; and-   R⁷ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₆—C₁₀ aryl, or optionally    substituted 5-10 membered heteroaryl;    or R⁶ and R⁷ together with the nitrogen to which they are attached    form an optionally substituted 4-7 membered heterocycle,-   provided that the compound is other than (i)    1H-Benzimidazole-7-carboxylic acid,    5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl- or (ii)    1H-Benzimidazole-7-carboxylic acid,    5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-.

In some embodiments, the compound is of formula (IA-1):

In one aspect, provided herein is a method of inhibiting tyrosine kinaseenzymatic activity of a protein selected from the group consisting ofAbelson protein (ABL1), Abelson-related protein (ABL2), and a chimericprotein BCR-ABL1, comprising contacting an effective amount of acompound or composition provided herein, to the protein.

In one aspect, provided herein is a method of treating a disease,wherein modulation of BCR-ABL1 activity prevents, inhibits, orameliorates the pathology and/or symptomology of the disease, in apatient, comprising administering to the patient a therapeuticallyeffective amount of a compound or composition provided herein.

In one aspect, provided herein is a method of treating leukemia in apatient comprising administering to the patient a therapeuticallyeffective amount of a compound or composition provided herein, whereinthe leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia(AML), or acute lymphoblastic leukemia (ALL).

DETAILED DESCRIPTION Definitions

As used herein, the following definitions shall apply unless otherwiseindicated. Further, if any term or symbol used herein is not defined asset forth below, it shall have its ordinary meaning in the art.

“Comprising” is intended to mean that the compositions and methodsinclude the recited elements, but not excluding others. “Consistingessentially of” when used to define compositions and methods, shall meanexcluding other elements of any essential significance to thecombination. For example, a composition consisting essentially of theelements as defined herein would not exclude other elements that do notmaterially affect the basic and novel characteristic(s) of the claimedinvention. “Consisting of” shall mean excluding more than trace amountof, e.g., other ingredients and substantial method steps recited.Embodiments defined by each of these transition terms are within thescope of this invention.

“Effective amount” or dose of a compound or a composition, refers tothat amount of the compound or the composition that results in anintended result as desired based on the disclosure herein. Effectiveamounts can be determined by standard pharmaceutical procedures in cellcultures or experimental animals, e.g., and without limitation, bydetermining the LD₅₀ (the dose lethal to 50% of the population) and theED₅₀ (the dose therapeutically effective in 50% of the population).

The term “excipient” as used herein means an inert or inactive substancethat may be used in the production of a drug or pharmaceutical, such asa tablet containing a compound of the invention as an active ingredient.Various substances may be embraced by the term excipient, includingwithout limitation any substance used as a binder, disintegrant,coating, compression/encapsulation aid, cream or lotion, lubricant,solutions for parenteral administration, materials for chewable tablets,sweetener or flavoring, suspending/gelling agent, or wet granulationagent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.;coatings include, e.g., cellulose acetate phthalate, ethylcellulose,gellan gum, maltodextrin, enteric coatings, etc.;compression/encapsulation aids include, e.g., calcium carbonate,dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose(anhydrate or monohydrate; optionally in combination with aspartame,cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.;disintegrants include, e.g., croscarmellose sodium, gellan gum, sodiumstarch glycolate, etc.; creams or lotions include, e.g., maltodextrin,carrageenans, etc.; lubricants include, e.g., magnesium stearate,stearic acid, sodium stearyl fumarate, etc.; materials for chewabletablets include, e.g., dextrose, fructose dc, lactose (monohydrate,optionally in combination with aspartame or cellulose), etc.;suspending/gelling agents include, e.g., carrageenan, sodium starchglycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame,dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulationagents include, e.g., calcium carbonate, maltodextrin, microcrystallinecellulose, etc.

“Patient” refers to mammals and includes humans and non-human mammals.Examples of patients include, but are not limited to mice, rats,hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows,and humans. In some embodiments, patient refers to a human.

“Pharmaceutically acceptable” refers to safe and non-toxic, preferablyfor in vivo, more preferably, for human administration.

“Pharmaceutically acceptable salt” refers to a salt that ispharmaceutically acceptable. A compound described herein may beadministered as a pharmaceutically acceptable salt.

“Prodrug” refers to a compound that, after administration, ismetabolized or otherwise converted to a biologically active or moreactive compound (or drug) with respect to at least one property. Aprodrug, relative to the drug, is modified chemically in a manner thatrenders it, relative to the drug, less active or inactive, but thechemical modification is such that the corresponding drug is generatedby metabolic or other biological processes after the prodrug isadministered. A prodrug may have, relative to the active drug, alteredmetabolic stability or transport characteristics, fewer side effects orlower toxicity, or improved flavor (for example, see the referenceNogrady, 1985, Medicinal Chemistry A Biochemical Approach, OxfordUniversity Press, New York, pages 388-392, incorporated herein byreference). A prodrug may be synthesized using reactants other thanemploying the corresponding drug. For illustration and withoutlimitation, prodrugs include, carboxy esters, linear and cyclicphosphate esters and phosphoramide and phosphoramidates, carbamates,preferably phenolic carbamates (i.e., carbamates where the hydroxy groupis part of an aryl or heteroaryl moiety, where the aryl and heteroarylmay be optionally substituted), and the likes.

“Salt” refers to an ionic compound formed between an acid and a base.When the compound provided herein contains an acidic functionality, suchsalts include, without limitation, alkali metal, alkaline earth metal,and ammonium salts. As used herein, ammonium salts include, saltscontaining protonated nitrogen bases and alkylated nitrogen bases.Exemplary and non-limiting cations useful in pharmaceutically acceptablesalts include Na, K, Rb, Cs, NH₄, Ca, Ba, imidazolium, and ammoniumcations based on naturally occurring amino acids. When the compoundsutilized herein contain basic functionality, such salts include, withoutlimitation, salts of organic acids, such as carboxylic acids andsulfonic acids, and mineral acids, such as hydrogen halides, sulfuricacid, phosphoric acid, and the likes. Exemplary and non-limiting anionsuseful in pharmaceutically acceptable salts include oxalate, maleate,acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate,mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.

“Therapeutically effective amount” or dose of a compound or acomposition refers to that amount of the compound or the compositionthat results in reduction or inhibition of symptoms or a prolongation ofsurvival in a patient. The results may require multiple doses of thecompound or the composition.

“Treating” or “treatment” of a disease in a patient refers to 1)preventing the disease from occurring in a patient that is predisposedor does not yet display symptoms of the disease; 2) inhibiting thedisease or arresting its development; or 3) ameliorating or causingregression of the disease. As used herein, “treatment” or “treating” isan approach for obtaining beneficial or desired results includingclinical results. For purposes of this disclosure, beneficial or desiredresults include, but are not limited to, one or more of the following:decreasing one more symptoms resulting from the disease or disorder,diminishing the extent of the disease or disorder, stabilizing thedisease or disorder (e.g., preventing or delaying the worsening of thedisease or disorder), delaying the occurrence or recurrence of thedisease or disorder, delay or slowing the progression of the disease ordisorder, ameliorating the disease or disorder state, providing aremission (whether partial or total) of the disease or disorder,decreasing the dose of one or more other medications required to treatthe disease or disorder, enhancing the effect of another medication usedto treat the disease or disorder, delaying the progression of thedisease or disorder, increasing the quality of life, and/or prolongingsurvival of a patient. Also encompassed by “treatment” is a reduction ofpathological consequence of the disease or disorder. The methods of theinvention contemplate any one or more of these aspects of treatment.

An “isotopomer” of a compound is a compound in which one or more atomsof the compound have been replaced with isotopes of those same atoms.For example, where H has been replaced by D or T, or ¹²C has beenreplaced by ¹¹C or ¹⁴N has been replaced by ¹⁵N. For example, andwithout limitation, replacement of with D can in some instances lead toreduced rates of metabolism and therefore longer half-lives. Replacementof H with T can provide radioligands potentially useful in bindingstudies. Replacement of ¹²C with the short-lived isotope ^(11C) canprovide ligands useful in Positron Emission Tomography (PET) scanning.Replacement of ¹⁴N with ¹⁵N provides compounds that can bedetected/monitored by ¹⁵N NMR spectroscopy. For example, an isotopomerof a compound containing —CH₂CH₃ is that compound but containing —CD₂CD₃instead of the —CH₂CH₃.

“Stereoisomer” or “stereoisomers” refer to compounds that differ in thestereogenicity of the constituent atoms such as, without limitation, inthe chirality of one or more stereocenters or related to the cis ortrans configuration of a carbon-carbon or carbon-nitrogen double bond.Stereoisomers include enantiomers and diastereomers.

“Tautomer” refer to alternate forms of a compound that differ in theposition of a proton, such as enol-keto and imine-enamine tautomers, orthe tautomeric forms of heteroaryl groups containing a ring atomattached to both a ring —NH— moiety and a ring=N-moiety such aspyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms,and more preferably from 1 to 6 carbon atoms. This term includes, by wayof example, linear and branched hydrocarbyl groups such as methyl(CH₃—), ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—), isopropyl (CH₃)₂CH—),n-butyl (CH₃CH₂CH₂CH₂—), isobutyl (CH₃)₂CHCH₂—), sec-butyl(CH₃)(CH₃CH₂)CH—), t-butyl (CH₃)₃C-), n-pentyl (CH₃CH₂CH₂CH₂CH₂—), andneopentyl (CH₃)₃CCH₂—). C_(x) alkyl refers to an alkyl group having xnumber of carbon atoms.

“Alkenyl” refers to straight or branched monovalent hydrocarbyl groupshaving from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms andhaving at least 1 and preferably from 1 to 2 sites of vinyl (>C═C<)unsaturation. Such groups are exemplified, for example, by vinyl, allyl,and but-3-en-1-yl. Included within this term are the cis and transisomers or mixtures of these isomers. C, alkenyl refers to an alkenylgroup having x number of carbon atoms.

“Alkynyl” refers to straight or branched monovalent hydrocarbyl groupshaving from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms andhaving at least 1 and preferably from 1 to 2 sites of acetylenic (—C≡C—)unsaturation. Examples of such alkynyl groups include acetylenyl(—C═CH), and propargyl (—CH₂C≡CH). C_(x) alkynyl refers to an alkynylgroup having x number of carbon atoms.

“Substituted alkyl” refers to an alkyl group having from 1 to 5,preferably 1 to 3, or more preferably 1 to 2 substituents selected fromthe group consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,substituted aryl, aryloxy, substituted aryloxy, arylthio, substitutedarylthio, arylamino, substituted arylamino, heteroarylamino, substitutedheteroarylamino, cycloalkylamino, substituted cycloalkylamino,heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxylester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl,substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy,cycloalkylthio, substituted cycloalkylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy,sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are defined herein.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 3substituents, and preferably 1 to 2 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,substituted aryl, aryloxy, substituted aryloxy, arylthio, substitutedarylthio, arylamino, substituted arylamino, heteroarylamino, substitutedheteroarylamino, cycloalkylamino, substituted cycloalkylamino,heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxylester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl,substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy,cycloalkylthio, substituted cycloalkylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy,sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are defined herein and with the proviso thatany hydroxy or thiol substitution is not attached to a vinyl(unsaturated) carbon atom.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 3substituents, and preferably 1 to 2 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,substituted aryl, aryloxy, substituted aryloxy, arylthio, substitutedarylthio, arylamino, substituted arylamino, heteroarylamino, substitutedheteroarylamino, cycloalkylamino, substituted cycloalkylamino,heterocycloalkylamino, substituted heterocyclylamino, carboxyl, carboxylester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl,substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy,cycloalkylthio, substituted cycloalkylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy,sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are defined herein and with the proviso thatany hydroxyl or thiol substitution is not attached to an acetyleniccarbon atom.

“Alkoxy” refers to the group —O-alkyl wherein alkyl is defined herein.Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

“Substituted alkoxy” refers to the group —O-(substituted alkyl) whereinsubstituted alkyl is defined herein. Preferred substituted alkyl groupsin —O-(substituted alkyl) include halogenated alkyl groups andparticularly halogenated methyl groups such as trifluoromethyl,difluromethyl, fluoromethyl and the like.

“Acyl” refers to the groups H—C(O)—, alkyl—C(O)—, substitutedalkyl—C(O)—, alkenyl—C(O)—, substituted alkenyl—C(O)—, alkynyl—C(O)—,substituted alkynyl—C(O)—, cycloalkyl—C(O)—, substitutedcycloalkyl—C(O)—, aryl—C(O)—, substituted aryl—C(O)—, heteroaryl—C(O)—,substituted heteroaryl—C(O)—, heterocyclic—C(O)—, and substitutedheterocyclic—C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic are as defined herein. Acyl includes the “acetyl” groupCH₃C(O)—.

“Acylamino” refers to the groups —NR³⁰C(O)alkyl, —NR³⁰C(O)substitutedalkyl, —NR³⁰C(O)cycloalkyl, —NR³⁰C(O)substituted cycloalkyl,—NR³⁰C(O)alkenyl, —NR³⁰C(O)substituted alkenyl, alkoxy, substitutedalkoxy-NR³⁰C(O)alkynyl, —NR³⁰C(O)substituted alkynyl, —NR³⁰C(O)aryl,—NR³⁰C(O)substituted aryl, —NR³⁰C(O)heteroaryl, —NR³⁰C(O)substitutedheteroaryl, —NR³⁰C(O)heterocyclic, and —NR³⁰C(O)substituted heterocyclicwherein R³⁰ is hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substitutedcycloalkyl; and wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups alkyl—C(O)O—, substituted alkyl—C(O)O—,alkenyl—C(O)O—, substituted alkenyl—C(O)O—, alkynyl—C(O)O—, substitutedalkynyl—C(O)O—, aryl—C(O)O—, substituted aryl—C(O)O—, cycloalkyl—C(O)O—,substituted cycloalkyl—C(O)O—, heteroaryl—C(O)O—, substitutedheteroaryl—C(O)O—, heterocyclic—C(O)O—, and substitutedheterocyclic—C(O)O— wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR³¹R³² where R³¹ and R³² areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, acylamino, substitutedacylamino, heteroarylamino, substituted heteroarylamino,cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino,substituted heterocyclylamino, sulfonylamino, and substituted sulfonyland wherein R³¹ and R³² are optionally joined, together with thenitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, provided that R³¹ and R³² are both not hydrogen, andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy,substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein. When R³¹ is hydrogen and R³² is alkyl, the substituted aminogroup is sometimes referred to herein as alkylamino. When R³¹ and R³²are alkyl, the substituted amino group is sometimes referred to hereinas dialkylamino. When referring to a monosubstituted amino, it is meantthat either R³¹ or R³² is hydrogen but not both. When referring to adisubstituted amino, it is meant that neither R³¹ nor R³² are hydrogen.

“Aminocarbonyl” refers to the group —C(O)NR³³R³⁴ where R³³ and R³⁴ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic and where R³³ and R³⁴ areoptionally joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic are as defined herein.

“Aminothiocarbonyl” refers to the group —C(S)NR³³R³⁴ where R³³ and R³⁴are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic and where R³³ and R³⁴ areoptionally joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic are as defined herein.

“Aminocarbonylamino” refers to the group —NR³⁰C(O)NR³³R³⁴ where R³⁰ ishydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R³³and R³⁴ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic andwhere R³³ and R³⁴ are optionally joined together with the nitrogen boundthereto to form a heterocyclic or substituted heterocyclic group, andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy,substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminothiocarbonylamino” refers to the group —NR³⁰C(S)NR³³R³⁴ where R³⁰is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, cycloalkyl, or substitutedcycloalkyl, and R³³ and R³⁴ are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic andwhere R³³ and R³⁴ are optionally joined together with the nitrogen boundthereto to form a heterocyclic or substituted heterocyclic group, andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy,substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminocarbonyloxy” refers to the group —O—C(O)NR^(33R34) where R³³ andR³⁴ are independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy,substituted alkoxy, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R³³ andR³⁴ are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy,substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminosulfonyl” refers to the group —SO₂NR³³R³⁴ where R³³ and R³⁴ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic and where R³³ and R³⁴ areoptionally joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic are as defined herein.

“Aminosulfonyloxy” refers to the group —O—SO₂NR³³R³⁴ where R³³ and R³⁴are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic and where R³³ and R³⁴ areoptionally joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic are as defined herein.

“Aminosulfonylamino” refers to the group —NR³⁰—SO₂NR³³R³⁴ where R³⁰ ishydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R³³and R³⁴ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic andwhere R³³ and R³⁴ are optionally joined together with the nitrogen boundthereto to form a heterocyclic or substituted heterocyclic group, andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy,substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Amidino” refers to the group —C(═NR³⁵)NR³³R³⁴ where R³³, R³⁴, and R³⁵are independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic and where R³³ and R³⁴ areoptionally joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic are as defined herein.

“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from6 to 14 carbon atoms having a single ring (e.g., phenyl (Ph)) ormultiple condensed rings (e.g., naphthyl or anthryl) which condensedrings may or may not be aromatic (e.g., 2-benzoxazolinone,2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the pointof attachment is at an aromatic carbon atom. Preferred aryl groupsinclude phenyl and naphthyl.

“Substituted aryl” refers to aryl groups which are substituted with 1 to5, preferably 1 to 3, or more preferably 1 to 2 substituents selectedfrom the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substitutedalkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino,substituted arylamino, heteroarylamino, substituted heteroarylamino,cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino,substituted heterocyclylamino carboxyl, carboxyl ester, (carboxylester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substitutedcycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio,substituted cycloalkylthio, guanidino, substituted guanidino, halo,hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substitutedheteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic,substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substitutedsulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, andsubstituted alkylthio, wherein said substituents are defined herein.

“Aryloxy” refers to the group —O-aryl, where aryl is as defined herein,that includes, by way of example, phenoxy and naphthoxy.

“Substituted aryloxy” refers to the group —O-(substituted aryl) wheresubstituted aryl is as defined herein.

“Arylthio” refers to the group —S-aryl, where aryl is as defined herein.

“Substituted arylthio” refers to the group —S-(substituted aryl), wheresubstituted aryl is as defined herein.

“Acylamino” refers to the group —NR³⁷(aryl), where aryl is as definedherein and R³⁷ is hydrogen, alkyl, or substituted alkyl.

“Substituted arylamino” refers to the group —NR³⁷(substituted aryl),where R³⁷ is hydrogen, alkyl, or substituted alkyl where substitutedaryl is as defined herein.

“Carbonyl” refers to the divalent group —C(O)— which is equivalent to—C(═(O)—.

“Carboxy” or “carboxyl” refers to —COOH or salts thereof.

“Carboxyl ester” or “carboxy ester” refers to the groups —C(O)O-alkyl,—C(O)O-substituted alkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl,—C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)O—cycloalkyl, —C(O)O-substitutedcycloalkyl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl,—C(O)O-heterocyclic, and —C(O)O-substituted heterocyclic wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein.

“(Carboxyl ester) amino” refers to the group —NR³⁰—C(O)O-alkyl,—NR³⁰—C(O)O-substituted alkyl, —NR³⁰—C(O)O-alkenyl,—NR³⁰—C(O)O-substituted alkenyl, —NR³⁰ 13 C(O)O-alkynyl,—NR³⁰—C(O)O-substituted alkynyl, —NR³⁰—C(O)O-aryl,—NR³⁰—C(O)O-substituted aryl, —NR³⁰—C(O)O-cycloalkyl,—NR³⁰—C(O)O-substituted cycloalkyl, —NR³⁰—C(O)O-heteroaryl,—NR³⁰—C(O)O-substituted heteroaryl, —NR³⁰—C(O)O-heterocyclic, and—NR³⁰—C(O)O-substituted heterocyclic wherein R³⁰ is alkyl or hydrogen,and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“(Carboxyl ester)oxy” refers to the group —O——C(O)O-alkyl,—O——C(O)O-substituted alkyl, —O——C(O)O-alkenyl, —O—C(O)O-substitutedalkenyl, —O—C(O)O-alkynyl, —O——C(O)O-substituted alkynyl,—O——C(O)O-aryl, —O—C(O)O-substituted aryl, —O—C(O)O-cycloalkyl,O——C(O)O-substituted cycloalkyl, —O—C(O)O-heteroaryl,—O—C(O)O-substituted heteroaryl, —O——C(O)O-heterocyclic, and—O——C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Cyano” refers to the group —C≡N.

“Cycloalkyl” refers to saturated or unsaturated but nonaromatic cyclicalkyl groups of from 3 to 10 carbon atoms, preferably from 3 to 8 carbonatoms, and more preferably from 3 to 6 carbon atoms, having single ormultiple cyclic rings including fused, bridged, and spiro ring systems.Cx cycloalkyl refers to a cycloalkyl group having x number of ringcarbon atoms. Examples of suitable cycloalkyl groups include, forinstance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, andcyclooctyl. One or more the rings can be aryl, heteroaryl, orheterocyclic provided that the point of attachment is through thenon-aromatic, non-heterocyclic ring saturated carbocyclic ring.“Substituted cycloalkyl” refers to a cycloalkyl group having from 1 to 5or preferably 1 to 3 substituents selected from the group consisting ofoxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, substituted amino, aminocarbonyl,aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino,amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio,substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino,(carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substitutedcycloalkylthio, guanidino, substituted guanidino, halo, hydroxy,heteroaryl, substituted heteroaryl, heteroaryloxy, substitutedheteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic,substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substitutedsulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substitutedalkylthio, wherein said substituents are defined herein.

“Cycloalkyloxy” refers to —O-cycloalkyl.

“Substituted cycloalkyloxy” refers to —O-(substituted cycloalkyl).

“Cycloalkylamino” refers to the group —NR³⁷(cycloalkyl) where R³⁷ ishydrogen, alkyl, or substituted alkyl.

“Substituted cycloalkylamino” refers to the group —NR³⁷(substitutedcycloalkyl) where R³⁷ is hydrogen, alkyl, or substituted alkyl andsubstituted cycloalkyl is as defined herein.

“Cycloalkylthio” refers to —S-cycloalkyl.

“Substituted cycloalkylthio” refers to —S-(substituted cycloalkyl).

“Guanidino” refers to the group —NHC(⊚NH)NH₂.

“Substituted guanidino” refers to —NR³⁶C(═NR³⁶)N(R³⁶)₂ where each R³⁶ isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and two R³⁶groups attached to a common guanidino nitrogen atom are optionallyjoined together with the nitrogen bound thereto to form a heterocyclicor substituted heterocyclic group, provided that at least one R³⁶ is nothydrogen, and wherein said substituents are as defined herein.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is fluoro or chloro.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroalkylene” refers to an alkylene group wherein one or more carbonsis replaced with —O—, —S—, SO₂, —NR^(Q)—,

moieties where R^(Q) is H or C₁—C₆ alkyl. “Substituted heteroalkylene”refers to heteroalkynylene groups having from 1 to 3 substituents, andpreferably 1 to 2 substituents, selected from the substituents disclosedfor substituted alkylene.

“Heteroaryl” refers to an aromatic group of from 1 to 10 carbon atomsand 1 to 4 heteroatoms selected from the group consisting of oxygen,nitrogen and sulfur within the ring. Such heteroaryl groups can have asingle ring (e.g., pyridinyl or furyl) or multiple condensed rings(e.g., indolizinyl or benzothienyl) wherein the condensed rings may ormay not be aromatic and/or contain a heteroatom provided that the pointof attachment is through an atom of the aromatic heteroaryl group. Inone embodiment, the nitrogen and/or the sulfur ring atom(s) of theheteroaryl group are optionally oxidized to provide for the N-oxide(N→O), sulfinyl, or sulfonyl moieties. Preferred heteroaryls include 5or 6 membered heteroaryls such as pyridinyl, pyrrolyl, thiophenyl, andfuranyl. Other preferred heteroaryls include 9 or 10 memberedheteroaryls, such as indolyl, quinolinyl, quinolonyl, isoquinolinyl, andisoquinolonyl.

“Substituted heteroaryl” refers to heteroaryl groups that aresubstituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to2 substituents selected from the group consisting of the same group ofsubstituents defined for substituted aryl.

“Heteroaryloxy” refers to —O-heteroaryl.

“Substituted heteroaryloxy” refers to the group —O-(substitutedheteroaryl).

“Heteroarylthio” refers to the group —S-heteroaryl.

“Substituted heteroarylthio” refers to the group —S-(substitutedheteroaryl).

“Heteroarylamino” refers to the group —NR³⁷(heteroaryl) where R³⁷ ishydrogen, alkyl, or substituted alkyl.

“Substituted heteroarylamino” refers to the group —NR³⁷(substitutedheteroaryl), where R³⁷ is hydrogen, alkyl, or substituted alkyl andsubstituted heteroaryl is defined as herein.

“Heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl”refers to a saturated or partially saturated, but not aromatic, grouphaving from 1 to 10 ring carbon atoms, preferably from 1 to 8 carbonatoms, and more preferably from 1 to 6 carbon atoms, and from 1 to 4ring heteroatoms, preferably from 1 to 3 heteroatoms, and morepreferably from 1 to 2 heteroatoms selected from the group consisting ofnitrogen, sulfur, or oxygen. C_(x) heterocycloalkyl refers to aheterocycloalkyl group having x number of ring atoms including the ringheteroatoms. Heterocycle encompasses single ring or multiple condensedrings, including fused bridged and spiro ring systems. In fused ringsystems, one or more the rings can be cycloalkyl, aryl or heteroarylprovided that the point of attachment is through the non-aromatic ring.In one embodiment, the nitrogen and/or sulfur atom(s) of theheterocyclic group are optionally oxidized to provide for the N-oxide,sulfinyl, sulfonyl moieties.

“Heterocyclylene” refers to a divalent saturated or partially saturated,but not aromatic, group having from 1 to 10 ring carbon atoms and from 1to 4 ring heteroatoms selected from the group consisting of nitrogen,sulfur, or oxygen. “Substituted heterocyclylene” refers toheterocyclylene groups that are substituted with from 1 to 5 orpreferably 1 to 3 of the same substituents as defined for substitutedcycloalkyl

“Substituted heterocyclic” or “substituted heterocycloalkyl” or“substituted heterocyclyl” refers to heterocyclyl groups that aresubstituted with from 1 to 5 or preferably 1 to 3 of the samesubstituents as defined for substituted cycloalkyl.

“Heterocyclyloxy” refers to the group —O-heterocycyl.

“Substituted heterocyclyloxy” refers to the group —O-(substitutedheterocycyl).

“Heterocyclylthio” refers to the group —S-heterocycyl.

“Substituted heterocyclylthio” refers to the group —S-(substitutedheterocycyl).

“Heterocyclylamino” refers to the group —NR³⁷(heterocyclyl) where R³⁷ ishydrogen, alkyl, or substituted alkyl.

“Substituted heterocyclylamino” refers to the group —NR³⁷(substitutedheterocyclyl), where R³⁷ is hydrogen, alkyl, or substituted alkyl andsubstituted heterocyclyl is defined as herein.

Examples of heterocyclyl and heteroaryl include, but are not limited to,azetidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl,pyrimidyl, pyridazyl, indolizyl, isoindolyl, indolyl, dihydroindolyl,indazolyl, purinyl, quinolizinyl, isoquinolinyl, quinolinyl,phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl,phenanthrolinyl, isothiazolyl, phenazinyl, isoxazolyl, phenoxazinyl,phenothiazinyl, imidazolidinyl, imidazolinyl, piperidinyl, piperazinyl,indolinyl, phthalimidyl, 1,2,3,4-tetrahydroisoquinolinyl,4,5,6,7-tetrahydrobenzo[b]thiophenyl, thiazolyl, thiazolidinyl,thiophenyl, benzo[b]thiophenyl, morpholinyl, thiomorpholinyl (alsoreferred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl,pyrrolidinyl, and tetrahydrofuranyl.

“Nitro” refers to the group —NO₂.

“Oxo” refers to the atom (═O) or (O).

“Spiro ring systems” refers to bicyclic ring systems that have a singlering carbon atom common to both rings.

“Sulfinyl” refers to the divalent group —S(O)— or —S(═O)—.

“Sulfonyl” refers to the divalent group —S(O)₂— or —S(═O)₂—.

“Substituted sulfonyl” refers to the group —SO₂-alkyl, —SO₂-substitutedalkyl, —SO₂—OH, —SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-cycloalkyl,—SO₂-substituted cylcoalkyl, —SO₂-aryl, —SO₂-substituted aryl,—SO₂-heteroaryl, —SO₂-substituted heteroaryl, —SO₂-heterocyclic,—SO₂-substituted heterocyclic, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein. Substituted sulfonyl includes groups such as methyl-SO₂—,phenyl-SO₂—, and 4-methylphenyl-SO₂—. Preferred substituted alkyl groupson the substituted alkyl-SO₂- include halogenated alkyl groups andparticularly halogenated methyl groups such as trifluoromethyl,difluromethyl, fluoromethyl and the like.

“Substituted sulfinyl” refers to the group —SO-alkyl, —SO-substitutedalkyl, —SO-alkenyl, —SO-substituted alkenyl, —SO-cycloalkyl,—SO-substituted cylcoalkyl, —SO-aryl, —SO-substituted aryl,—SO-heteroaryl, —SO-substituted heteroaryl, —SO-heterocyclic,—SO-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein. Substituted sulfinyl includes groups such as methyl-SO—,phenyl-SO—, and 4-methylphenyl-SO—. Preferred substituted alkyl groupson the substituted alkyl-SO— include halogenated alkyl groups andparticularly halogenated methyl groups such as trifluoromethyl,difluromethyl, fluoromethyl and the like.

“Sulfonyloxy” or “substituted sulfonyloxy” refers to the group—OSO₂-alkyl, —OSO₂-substituted alkyl, —OSO₂—OH, —OSO₂-alkenyl,—OSO₂-substituted alkenyl, —OSO₂-cycloalkyl, —OSO₂-substitutedcylcoalkyl, —OSO₂-aryl, —OSO₂-substituted aryl, —OSO₂-heteroaryl,—OSO₂-substituted heteroaryl, —OSO₂-heterocyclic, —OSO₂-substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic are as defined herein.

“Sulfonylamino” refers to the group —NR³⁷(substituted sulfonyl) whereR³⁷ is hydrogen, alkyl, or substituted alkyl and substituted sulfonyl isas defined here.

“Thioacyl” refers to the groups H—C(S)—, alkyl—C(S)—, substitutedalkyl—C(S)—, alkenyl—C(S)—, substituted alkenyl—C(S)—, alkynyl—C(S)—,substituted alkynyl—C(S)—, cycloalkyl—C(S)—, substitutedcycloalkyl—C(S)—, aryl—C(S)—, substituted aryl—C(S)—, heteroaryl—C(S)—,substituted heteroaryl—C(S)—, heterocyclic—C(S)—, and substitutedheterocyclic—C(S)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Mercapto” or “thiol” refers to the group —SH.

“Formyl” refers to the group —C(O)H.

“Thiocarbonyl” refers to the divalent group —C(S)— which is equivalentto —C(═S)—.

“Thione” refers to the atom (═S).

“Alkylthio” refers to the group —S-alkyl wherein alkyl is as definedherein.

“Substituted alkylthio” refers to the group —S-(substituted alkyl)wherein substituted alkyl is as defined herein. Preferred substitutedalkyl groups on —S-(substituted alkyl) include halogenated alkyl groupsand particularly halogenated methyl groups such as trifluoromethyl,difluromethyl, fluoromethyl and the like.

“Vinyl” refers to unsaturated hydrocarbon radical —CH═CH₂, derived fromethylene.

The terms “optional” or “optionally” as used throughout thespecification means that the subsequently described event orcircumstance may but need not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not. For example, “the nitrogen atom is optionally oxidized toprovide for the N-oxide (N→O) moiety” means that the nitrogen atom maybut need not be oxidized, and the description includes situations wherethe nitrogen atom is not oxidized and situations where the nitrogen atomis oxidized.

The term “optionally substituted” refers to a substituted orunsubstituted group. The substituted group may be substituted with oneor more substituents, such as e.g., 1, 2, 3, 4 or 5 substituents.Preferably, the substituents are selected from the functional groupsprovided herein. In certain more preferred embodiments, the substituentsare selected from oxo, halo, —CN, NO₂, —CO₂R¹⁰⁰, —OR¹⁰⁰, —OR¹⁰⁰, —SR¹⁰⁰,—SOR¹⁰⁰, —SO₂R¹⁰⁰, —NR¹⁰¹R¹⁰², —CONR¹⁰¹R¹⁰², —SO₂NR¹⁰¹R¹⁰², C₁—C₆alkoxy, —CR¹⁰⁰═C(R¹⁰⁰)₂, —CCR¹⁰⁰, C₃—C₁₀ cycloalkyl, C₄—C₁₀heterocyclyl, C₆—C₁₄ aryl and C₅—C₁₂ heteroaryl, wherein each R¹⁰⁰independently is hydrogen or C₁—C₈ alkyl; C₃—C₁₂ cycloalkyl; C₄—C₁₀heterocyclyl; C₆—C₁₄ aryl; or C₂—C₁₂ heteroaryl; wherein each alkyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substitutedwith 1-3 halo, 1-3 C₁—C₆ alkyl, 1-3 C₁—C₆ haloalkyl or 1-3 C₁—C₆ alkoxygroups. More preferably, the substituents are selected from the groupconsisting of chloro, fluoro, —OCH₃, methyl, ethyl, iso-propyl,cyclopropyl, —OCF₃, —CF₃ and —OCHF₂.

R¹⁰¹ and R¹⁰² independently are hydrogen; C₁—C₈ alkyl, optionallysubstituted with —CO₂H or an ester thereof, C₁—C₆ alkoxy, oxo,—CR¹⁰³═C(R¹⁰³)₂, —CCR, C₃—C₁₀ cycloalkyl, C₃—C₁₀ heterocyclyl, C₆—C₁₄aryl, or C₂—C₁₂ heteroaryl, wherein each R¹⁰³ independently is hydrogenor C₁—C₈ alkyl; C₃—C₁₂ cycloalkyl; C₄—C₁₀ heterocyclyl; C₆—C₁₄ aryl; orC₂—C₁₂ heteroaryl; wherein each cycloalkyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with 1-3 alkyl groups or 1-3 halogroups, or R¹⁰¹ and R¹⁰² together with the nitrogen atom they areattached to form a 5-7 membered heterocycle.

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. For example, the substituent“alkoxycarbonylalkyl” refers to the group (alkoxy)—C(O)-(alkyl)-.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,etc.) are not intended for inclusion herein. In such cases, the maximumnumber of such substituents is three. That is to say that each of theabove definitions is constrained by a limitation that, for example,substituted aryl groups are limited to—substituted aryl-(substitutedaryl)-substituted aryl.

In some embodiments of a substituted moiety, the moiety is substitutedwith a group that may also be substituted with a further group, but thefurther group cannot be additionally substituted. For example, in someembodiments of “substituted alkyl”, the alkyl moiety is substituted witha group that may be further substituted (e.g., substituted alkoxy,substituted amino, substituted aryl, substituted aryloxy, substitutedarylthio, substituted acylamino, substituted heteroarylamino,substituted cycloalkylamino, substituted heterocyclylamino, substitutedcycloalkyl, substituted cycloalkyloxy, substituted cycloalkylthio,substituted guanidino, substituted heteroaryl, substitutedheteroaryloxy, substituted heteroarylthio, substituted heterocyclic,substituted heterocyclyloxy, substituted heterocyclylthio, substitutedsulfonyl, substituted alkylthio), but the substituted alkoxy,substituted amino, substituted aryl, substituted aryloxy, substitutedarylthio, substituted acylamino, substituted heteroarylamino,substituted cycloalkylamino, substituted heterocyclylamino, substitutedcycloalkyl, substituted cycloalkyloxy, substituted cycloalkylthio,substituted guanidino, substituted heteroaryl, substitutedheteroaryloxy, substituted heteroarylthio, substituted heterocyclic,substituted heterocyclyloxy, substituted heterocyclylthio, substitutedsulfonyl or substituted alkylthio on the alkyl moiety is not substitutedwith a moiety that is itself further substituted. Although “substitutedalkyl” is provided as an example, such an embodiment is intended foreach substituted moiety described herein.

In some embodiments of a substituted moiety, the moiety is substitutedwith a group that is not further substituted. Thus, in some embodiments,“substituted alkyl” is an alkyl moiety substituted with one or more, andin some aspects, 1 or 2 or 3 or 4 or 5 moieties independently selectedfrom the group consisting of alkoxy, acyl, acylamino, acyloxy, amino,aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, aryloxy, arylthio,arylamino, heteroarylamino, cycloalkylamino, heterocycloalkylamino,carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy,cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, guanidino, halo,hydroxy, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic,heterocyclyloxy, heterocyclylthio, nitro, SO₃H, sulfonyloxy,sulfonylamino, thioacyl, thiol, and alkylthio. Although “substitutedalkyl” is provided as an example, such an embodiment is intended foreach substituted moiety described herein.

It is understood that the above definitions are not intended to includeimpermissible substitution patterns (e.g., methyl substituted with 4fluoro groups). Such impermissible substitution patterns are well knownto the skilled artisan.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables arespecifically embraced by the present invention and are disclosed hereinjust as if each and every combination was individually and explicitlydisclosed, to the extent that such combinations embrace compounds thatare stable compounds (i.e., compounds that can be isolated,characterized, and tested for biological activity). In addition, allsubcombinations of the chemical groups listed in the embodimentsdescribing such variables are also specifically embraced by the presentinvention and are disclosed herein just as if each and every suchsub-combination of chemical groups was individually and explicitlydisclosed herein.

Compounds

In one aspect, is provided a compound of formula (I):

or a tautomer or an N-oxide thereof, or an isotopomer of each thereof,or a prodrug of each of the above, or a stereoisomer of the aforesaid,or a pharmaceutically acceptable salt of each of the foregoing, or asolvate of each of the preceding, wherein:

-   L is —NH—CO—, —CO—NH—, —NH—SO₂—, or —SO₂—NH—;-   R¹ is optionally substituted C₆—C₁₀ aryl, optionally substituted    5-10 membered heteroaryl, optionally substituted 4-10 membered    heterocycle, C(O)NR⁶R⁷, S(O)₂NR⁶R⁷, NR⁶COR⁷, or NR⁶SO₂R⁷, or    C(O)OR⁶;-   R² is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₂—C₆ alkenyl, optionally    substituted C₂—C₆ alkynyl, optionally substituted C₆—C₁₀ aryl, or    optionally substituted 5-10 membered heteroaryl;-   R³ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₂—C₆ alkenyl, optionally substituted C₂—C₆ alkynyl, optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl,    optionally substituted aryl, optionally substituted heteroaryl, OR⁶,    or NR⁶R⁷; or

R² and R³ together with the intervening atoms form cycloalkyl orheterocycloalkyl, preferably an optionally substituted C₃—C₈ cycloalkylor an optionally substituted 4-10 membered heterocycloalkyl;

R⁴ is optionally substituted C₁—C₆ alkyl, preferably C₁—C₃ haloalkyl,such as CF₃ or CF₂Cl, optionally substituted C₂—C₆ alkenyl, optionallysubstituted C₂—C₆ alkynyl;

-   X is O or S;-   Y is CH, C—(C₁—C₂ alkyl), or C-halo or N;-   Z is CR⁵ or N;-   R⁵ is H or halogen;-   R⁶ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₆—C₁₀ aryl, or optionally    substituted 5-10 membered heteroaryl; and-   R⁷ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₆—C₁₀ aryl, or optionally    substituted 5-10 membered heteroaryl; or-   R⁶ and R⁷ together with the nitrogen to which they are attached form    an optionally substituted 4-7 membered heterocycle,-   provided that the compound is other than (i)    1H-Benzimidazole-7-carboxylic acid,    5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl- or (ii)    1H-Benzimidazole-7-carboxylic acid,    5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-.

In some embodiments, provided is a compound of formula (I-i):

or a tautomer or an N-oxide thereof, or an isotopomer of each thereof,or a prodrug of each of the above, or a stereoisomer of the aforesaid,or a pharmaceutically acceptable salt of each of the foregoing, or asolvate of each of the preceding, wherein:

-   L is —NH—CO—, —CO—NH—, or —NH—SO₂—;-   R¹ is optionally substituted C₆—C₁₀ aryl, optionally substituted    5-10 membered heteroaryl, optionally substituted 4-10 membered    heterocycle, C(O)NR⁶R⁷, S(O)₂NR⁶R⁷, NR⁶COR⁷, or NR⁶SO₂R⁷, or    C(O)OR⁶;-   R² is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₂—C₆ alkenyl, optionally    substituted C₂—C₆ alkynyl, optionally substituted C₆—C₁₀ aryl, or    optionally substituted 5-10 membered heteroaryl;-   R³ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₂—C₆ alkenyl, optionally substituted C₂—C₆ alkynyl, optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl,    optionally substituted aryl, optionally substituted heteroaryl, OR⁶,    or NR⁶R⁷; or-   R² and R³ together with the intervening atoms form cycloalkyl or    heterocycloalkyl, preferably an optionally substituted C₃—C₈    cycloalkyl or an optionally substituted 4-10 membered    heterocycloalkyl;-   R⁴ is optionally substituted C₁—C₆ alkyl, preferably C₁—C₃    haloalkyl, such as CF3 or CF₂Cl, optionally substituted C₂—C₆    alkenyl, optionally substituted C₂—C₆ alkynyl;-   X is O or S;-   Y is CH, C—(C₁—C₂ alkyl), or C-halo or N;-   Z is CR⁵ or N;-   R⁵ is H or halogen;-   R⁶ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₆—C₁₀ aryl, or optionally    substituted 5-10 membered heteroaryl; and-   R⁷ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₆—C₁₀ aryl, or optionally    substituted 5-10 membered heteroaryl; or-   R⁶ and R⁷ together with the nitrogen to which they are attached form    an optionally substituted 4-7 membered heterocycle.

Also provided herein is a compound of formula (I-a):

wherein R¹, R², R³, R⁴, X, Y, Z, and L are as defined for the compoundof formula (I).

In some embodiments, the compound is of formula (IA):

It is understood that when Z is N, then R⁵ is absent. Similarly, it isunderstood that when R⁵ is present, then R⁵ is bound to a carbon atom inthe aryl ring such that Z is CR⁵.

In some embodiments, the compound is of formula (IA-1):

In some embodiments, the compound is selected from formula (IIA)-(IIH):

wherein R¹⁰ is an optionally substituted 5-6 membered heteroaryl,preferably the heteroaryl moiety has up to 2 ring nitrogen atoms;

-   R²⁰ is optionally substituted C₁—C₃ alkyl, optionally substituted    C₃—C₄ cycloalkyl, or optionally substituted 4-6 membered    heterocycloalkyl, preferably, R²⁰ is methyl, optionally substituted    isopropyl, or cyclopropyl;-   R³⁰ H, optionally substituted C₁—C₃ alkyl, optionally substituted    C₃—C₄ cycloalkyl, or optionally substituted 5-6 membered    heterocycloalkyl, preferably optionally substituted cyclopropyl;-   Ring A is optionally substituted 5-6 membered heterocycloalkyl; and-   the remaining variables are defined as herein.

In some embodiments, the compound is of formula (IIA):

In some embodiments, the compound is of formula (IIB):

In some embodiments, the compound is of formula (IIC):

In some embodiments, the compound is of formula (IID):

In some embodiments, the compound is of formula (IIE):

In some embodiments, the compound provided herein is of formula (IIF):

In some embodiments, the compound provided herein is of formula (IIG):

In some embodiments, the compound provided herein is of formula (IIH):

In some embodiments, the compound provided herein is of formula (Ib):

wherein the remaining variables are defined as herein.

In some embodiments, the compound provided herein is of formula (Ic):

wherein the remaining variables are defined as herein.

In some embodiments, the compound provided herein is of formula (Id) or(Ie):

wherein the remaining variables are defined as herein.

In some embodiments, L is —NH—CO—. In some embodiments, L is —CO—NH—. Insome embodiments, L is —NH-SO₂—. In some embodiments, L is —SO₂—NH—.

In some embodiments, R¹ is optionally substituted C₆—C₁₀ aryl. In someembodiments, R¹ is optionally substituted 5-10 membered heteroaryl. Insome embodiments, R¹ is optionally substituted 4-10 memberedheterocycle. In some embodiments, R¹ is C(O)NR⁶R⁷. In some embodiments,R¹ is S(O)₂NR⁶R⁷. In some embodiments, R¹ is NR⁶COR⁷. In someembodiments, R¹ is or NR⁶SO₂R⁷. In some embodiments, R¹ is C(O)OR⁶.

In some embodiments, R² is H. In some embodiments, R² is optionallysubstituted C₁—C₆ alkyl. In some embodiments, R² is cycloalkylalkyl. Insome embodiments, R² is heterocyclylalkyl. In some embodiments, R² isarylalkyl. In some embodiments, R² is heteroarylalkyl. In someembodiments, R² is optionally substituted C₃—C₈ cycloalkyl. In someembodiments, R² is optionally substituted 4-10 memberedheterocycloalkyl. In some embodiments, R² is optionally substitutedC₂—C₆ alkenyl. In some embodiments, R² is optionally substituted C₂—C₆alkynyl. In some embodiments, R² is optionally substituted C₆—C₁₀ aryl.In some embodiments, R² is optionally substituted 5-10 memberedheteroaryl.

In some embodiments, R³ is H. In some embodiments, R³ is optionallysubstituted C₁—C₆ alkyl. In some embodiments, R³ is optionallysubstituted C₂—C₆ alkenyl. In some embodiments, R³ is optionallysubstituted C₂—C₆ alkynyl. In some embodiments, R³ is optionallysubstituted cycloalkyl. In some embodiments, R³ is optionallysubstituted heterocycloalkyl. In some embodiments, R³ is optionallysubstituted 4-6 membered heterocycloalkyl. In some embodiments, R³ isoptionally substituted aryl. In some embodiments, R³ is optionallysubstituted C₆—C₁₀ aryl. In some embodiments, R³ is optionallysubstituted heteroaryl. In some embodiments, R³ is optionallysubstituted 5-10 membered heteroaryl. In some embodiments, R³ is C₁—C₆alkyl, C₂—C₆ alkenyl, C₂—C₆ alkynyl, C₃—C₆ cycloalkyl, 4- to 6-memberedheterocycloalkyl, C₆—C₁₀ aryl, or 5- to 10-membered heteroaryl, each ofwhich is optionally substituted by 1-3 substituents selected from thegroup consisting of halogen, hydroxyl, and C₁—C₆ alkyl. In someembodiments, R³ is OR⁶. In some embodiments, R³ is NR⁶R⁷.

In some embodiments, R² and R³ together with the intervening atoms formring A, which is cycloalkyl. It is understood that R² and R³ takentogether with the intervening atoms to form ring A, which is cycloalkyl,does not include the nitrogen atom to which R² is attached. Rather, itis understood that no further heteroatoms, other than the nitrogen atomto which R² is attached, make up ring A. In some embodiments, R² and R³together with the intervening atoms form ring A, which isheterocycloalkyl. It is understood that R² and R³ taken together withthe intervening atoms to form ring A, which is heterocycloalkyl,includes the nitrogen atom to which R² is attached. It is alsounderstood that additional heteroatoms, further to the nitrogen atom towhich R² is attached, can make up ring A. In some embodiments, R² and R³are taken together with the intervening atoms to form ring A, which isheterocycloalkyl, and does not include any heteroatoms other than thenitrogen atom to which R² is attached. In some embodiments, R² and R³are taken together with the intervening atoms to form ring A, which isheterocycloalkyl, and includes the nitrogen atom to which R² is attachedas well as additional heteroatoms. In some embodiments, R² and R³together with the intervening atoms form ring A, which is an optionallysubstituted C₃—C₈ cycloalkyl. Suitable cycloalkyl substituents include,without limitation, C₁—C₆ alkyl, hydroxyC₁—C₆ alkyl, and C₁—C₆ alkylsubstituted with 1-3 halo, preferably fluoro atoms. In some embodiments,R² and R³ together with the intervening atoms form ring A, which is anoptionally substituted 4-10 membered heterocycloalkyl. Suitableheterocycloalkyl substituents include, without limitation C₁—C₆ alkyl,hydroxyC₁—C₆ alkyl, and C₁—C₆ alkyl substituted with 1-3 halo,preferably fluoro atoms.

In some embodiments, R⁴ is optionally substituted C₁—C₆ alkyl. In someembodiments, R⁴ is C₁—C₃ haloalkyl. In some embodiments, R⁴ is CF₃. Insome embodiments, R⁴ is CF₂Cl. In some embodiments, R⁴ is optionallysubstituted C₂—C₆ alkenyl. In some embodiments, R⁴ is optionallysubstituted C₂—C₆ alkynyl.

In some embodiments, X is O. In some embodiments, X is S.

In some embodiments, Y is CH. In some embodiments, Y is C—(C₁—C₂ alkyl).In some embodiments, Y is C-halo. In some embodiments, Y is N.

In some embodiments, Z is CR⁵. In some embodiments, Z is N.

In some embodiments, R⁵ is H. In some embodiments, R⁵ is halogen.

In some embodiments, R⁶ is H. In some embodiments, R⁶ is optionallysubstituted C₁—C₆ alkyl. In some embodiments, R⁶ is optionallysubstituted C₃—C₈ cycloalkyl. In some embodiments, R⁶ is optionallysubstituted 4-10 membered heterocycloalkyl. In some embodiments, R⁶ isoptionally substituted C₆—C₁₀ aryl. In some embodiments, R⁶ isoptionally substituted 5-10 membered heteroaryl. In some embodiments, R⁶is C₁—C₆ alkyl, C₃—C₈ cycloalkyl, 4-10 membered heterocycloalkyl, C₆—C₁₀aryl, or 5-10 membered heteroaryl, each of which is optionallysubstituted by 1-3 substituents selected from the group consisting ofhalogen, hydroxyl, and C₁—C₆ alkyl.

In some embodiments, R⁷ is H. In some embodiments, R⁷ is optionallysubstituted C₁—C₆ alkyl. In some embodiments, R⁷ is optionallysubstituted C₃—C₈ cycloalkyl. In some embodiments, R⁷ is optionallysubstituted 4-10 membered heterocycloalkyl. In some embodiments, R⁷isoptionally substituted C₆—C₁₀ aryl. In some embodiments, R⁷is optionallysubstituted 5-10 membered heteroaryl. In some embodiments, R⁷ is C₁—C₆alkyl, C₃—C₈ cycloalkyl, 4-10 membered heterocycloalkyl, C₆—C₁₀ aryl, or5-10 membered heteroaryl, each of which is optionally substituted by 1-3substituents selected from the group consisting of halogen, hydroxyl,and C₁—C₆ alkyl.

In some embodiments, R⁶ is H; and R⁷ is H, optionally substituted C₁—C₆alkyl, optionally substituted C₃—C₈ cycloalkyl, optionally substituted4-10 membered heterocycloalkyl, optionally substituted C₆—C₁₀ aryl, oroptionally substituted 5-10 membered heteroaryl.

In some embodiments, R⁶ and R⁷ together with the nitrogen to which theyare attached form an optionally substituted 4-7 membered heterocycle. Insome embodiments, R⁶ and R⁷ together with the nitrogen to which they areattached form 4-7 membered heterocycle optionally substituted by 1-3substituents selected from the group consisting of halogen, hydroxyl,and C₁—C₆ alkyl.

In some embodiments, R¹⁰ is a 5-6 membered heteroaryl. In someembodiments, R¹⁰ is a 5-6 membered heteroaryl, wherein the heteroarylmoiety has up to 2 ring nitrogen atoms. In some embodiments, R¹⁰ is 5-6membered heteroaryl optionally substituted by 1-3 substituents selectedfrom the group consisting of halogen, cyano, hydroxyl, C₁—C₆ alkoxy,C₁—C₆ alkyl, and C₃—C₆ cycloalkyl.

In some embodiments, R²⁰ is optionally substituted C₁—C₃ alkyl. In someembodiments, R²⁰ is optionally substituted C₃—C₄ cycloalkyl. In someembodiments, R²⁰ is methyl. In some embodiments, R²⁰ is optionallysubstituted isopropyl. In some embodiments, R²⁰ is cyclopropyl. In someembodiments, R²⁰ is C₁—C₃ alkyl, C₃—C₄ cycloalkyl, or 4-6 memberedheterocycloalkyl, each of which is optionally substituted by 1-3substituents selected from the group consisting of halogen, hydroxyl,C₁—C₆ alkoxy, C₁—C₆ alkyl, C₃—C₆ cycloalkyl, 4- to 6-memberedheterocyclyl, cyano, oxo, —C(O)NH(C₁—C₆ alkyl), and —C(O)NH(C₃—C₆cycloalkyl),In some embodiments, R³⁰ is H. In some embodiments, R³⁰ isoptionally substituted C₁—C₃ alkyl. In some embodiments, R³⁰ isoptionally substituted C₃—C₄ cycloalkyl. In some embodiments, R³⁰ isoptionally substituted cyclopropyl. In some embodiments, R³⁰ is C₁—C₃alkyl, C₃—C₄ cycloalkyl, or 5-6 membered heterocycloalkyl, each of whichis optionally substituted by 1-3 substituents selected from the groupconsisting of halogen, hydroxyl, and C₁—C₆ alkyl.

In some embodiments, R¹ is a 5-6 membered heteroaryl. In someembodiments, R¹ is a 5-6 membered heteroaryl containing up to 2 ringnitrogen atoms. In some embodiments, R¹ is a 5-6 membered heteroarylcontaining 2 ring nitrogen atoms. In some embodiments, R¹ is a 5-6membered heteroaryl containing 1 ring nitrogen atom. In someembodiments, R¹ is a 5-6 membered heteroaryl containing 3 ring nitrogenatoms. In some embodiments, R¹ is pyrimidinyl. In some embodiments, R¹is pyrazolyl. In some embodiments, R¹ is pyridyl. In some embodiments,R¹ is triazolyl. In some embodiments, R¹ is imidazolyl. In someembodiments, R¹ is pyridazinyl. In some embodiments, R¹ is a 5-6membered heteroaryl containing 1 ring nitrogen atom and 1 ring sulfuratom. In some embodiments, R¹ is a 5-6 membered heteroaryl containing 1ring nitrogen atom and 1 ring oxygen atom. In some embodiments, R¹ isthiazolyl. In some embodiments, R¹ is oxazolyl. In some embodiments, R¹is isothiazolyl. In some embodiments, R¹ is isoxazolyl. In someembodiments, R¹ is a 4-5 membered heterocyclyl containing 1 ringnitrogen atom. In some embodiments, R¹ is a 4-5 membered heterocyclylwhich is optionally substited by 1-2 oxo groups. In some embodiments, R¹is azetidinyl. In some embodiments, R¹ is pyrrolidinyl. In any of theseembodiments, R¹ is optionally substituted by 1-3 substituents selectedfrom the group consisting of halogen, cyano, hydroxyl, C₁—C₆ alkoxy,C₁—C₆ alkyl, and C₃—C₆ cycloalkyl. In some variations, R¹ is substitutedby 1-2 substituents selected from the group consisting of halogen,cyano, hydroxyl, C₁—C₃ alkoxy, C₁—C₃ alkyl, and C₃—C₆ cycloalkyl. Insome variations, R¹ is substituted by 1 substituent selected from thegroup consisting of halogen, cyano, hydroxyl, C₁—C₃ alkoxy, C₁—C₃ alkyl,and C₃—C₆ cycloalkyl. In some variations, R¹ is substituted by 1substituent selected from the group consisting of fluoro, chloro, bromo,cyano, hydroxyl, methoxy, ethoxy, methyl, ethyl, cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ —CONHR⁷, wherein R⁷ is H, C₃—C₆ cycloalkyl, orC₁—C₆ alkyl.

In some embodiments, R¹ is —CONH(C₃—C₆ cycloalkyl). In some embodiments,R¹ is

—CONH(C₃—C₅ cycloalkyl). In some embodiments, R¹ is —CONH(C₃—C₄cycloalkyl).

In some embodiments, R¹ is —CONH(cyclopropyl).

In some embodiments, R¹ is —CONH₂.

In some embodiments, R¹ is —CONH(C₁—C₆ alkyl). In some embodiments, R₁is —CONH(C₁—C₃ alkyl). In some embodiments, R¹ is —CON(H)(CH₃) or—CON(H)(C₂H₅).

In some embodiments, R² is optionally substituted C₁—C₃ alkyl. In someembodiments, R² is methyl. In some embodiments, R² is ethyl. In someembodiments, R² is propyl. In some embodiments, R² is optionallysubstituted isopropyl. In some embodiments, R² is isopropyl. In someembodiments, R² is butyl. In some embodiments, R² is tertiary butyl. Insome embodiments, R² is pentyl. In some embodiments, R² is n-pentyl,sec-pentyl, 3-pentyl, or sec-isopentyl. In some embodiments, R² isoptionally substituted C₃—C₄ cycloalkyl. In some embodiments, R² iscyclopropyl. In some embodiments, R² is cyclobutyl. In some embodiments,R² is cyclopentyl. In some embodiments, R² is 4- to 6-memberedheterocyclyl. In some embodiments, R² is 4- to 6-membered heterocyclylcontaining 1 or 2 heteroatoms selected from the group consisting ofnitrogen, sulfur, and oxygen. In some embodiments, R² istetrahydrofuranyl. In some embodiments, R² is tetrahydropyranyl. In someembodiments, R² is thietanyl. In some embodiments, R² is pyrrolidinyl.In any of these embodiments, R² is optionally substituted by 1-3substituents selected from the group consisting of halogen, hydroxyl,C₁—C₆ alkoxy, C₁—C₆ alkyl, C₃—C₆ cycloalkyl, 4- to 6-memberedheterocyclyl, cyano, oxo, —C(O)NH(C₁—C₆ alkyl), and —C(O)NH(C₃—C₆cycloalkyl). In some variations, R² is substituted by 1-3 substituentsselected from the group consisting of halogen, hydroxyl, C₁—C₃ alkoxy,C₁—C₃ alkyl, C₃—C₅ cycloalkyl, 4- to 6-membered heterocyclyl, cyano,oxo, —C(O)NH(C₁—C₃ alkyl), and —C(O)NH(C₃—C₆ cycloalkyl). In somevariations, R² is substituted by 1-3 substituents selected from thegroup consisting of fluoro, chloro, bromo, hydroxyl, methyoxy, ethyoxy,methyl, ethyl, cyclopropyl, cyclobutyl, oxetanyl, cyano, oxo,—C(O)NH(CH₃), —C(O)NH(CH₂CH₃), —C(O)NH(cyclopropyl),—C(O)NH(cyclobutyl), —C(O)NH(cyclopentyl), and —C(O)NH(cyclohexyl).

In some embodiments, R² is H.

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² and R³ together with the intervening atoms formring A, which is optionally substituted 5- to 6-memberedheterocycloalkyl. In some embodiments, ring A is optionally substitutedby 1-3 substituents selected from the group consisting of C₁—C₆ alkyl,hydroxyl, C₁—C₆ alkyl-OH, —C(O)(C₁—C₆ alkyl), and oxo. In somevariations, ring A is substituted by 1-3 substituents selected from thegroup consisting of C₁—C₃ alkyl, hydroxyl, C₁—C₃ alkyl-OH, —C(O)(C₁—C₃alkyl), and oxo. In some variations, ring A is substituted by 1-3substituents selected from the group consisting of methyl, ethyl,hydroxyl, —CH₂OH, —CH₂CH₂—OH, —C(O)CH₃, —C(O)CH₂CH₃, and oxo.

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R² and R³ together form:

In some embodiments, R³ is H. In some embodiment, R³ is C₁—C₆ alkyloptionally substituted with 1-3 substituents selected from the groupconsisting of halogen, hydroxyl, and —O(C₁—C₆ alkyl). In someembodiments, R³ is methyl. In some embodiments, R³ is isopropyl. In someembodiments, R³ is difluoromethyl. In some embodiments, R³ ishydroxyethyl. In some embodiments, R³ is —CH₂CH₂OH. In some embodiments,R³ is —C(Me)₂OH. In some embodiments, R³ is —CH(Me)OH. In someembodiments, R³ is methoxymethyl. In some embodiments, R³ ishydroxymethyl. In some embodiments, R³ is C₃—C₆ cycloalkyl. In someembodiments, R³ is C₃—C₆ cycloalkyl substituted by 1-3 substituentsselected from the group consisting of halogen, C₁—C₆ alkyl, andhydroxyl. In some embodiments, R³ is cyclopropyl. In some embodiments,R³ is cyclobutyl. In some embodiments, R³ is —OR⁶, wherein R⁶ is C₁—C₆alkyl. In some embodiments, R³ is methoxy. In some embodiments, R³ isethoxy. In some embodiments, R³ is 4- to 6-membered heterocyclyl. Insome embodiments, R³ is 4- to 6-membered heterocyclyl substituted by 1-3substituents selected from the group consisting of halogen, C₁—C₆ alkyl,and hydroxyl. In some embodiments, R³ is tetrahydropyranyl.

In some embodiments, R⁴ is optionally substituted C₁—C₃ alkyl. In someembodiments, R⁴ is C₁—C₃ alkyl, wherein the alkyl group is substitutedwith one or more halo substituents. In some embodiments, R⁴ is C₁—C₃alkyl substituted with 1-3 halo substituents. In some embodiments, R⁴ isCF₃. In some embodiments, R⁴ is CF₂Cl.

In one aspect, provided is a compound of formula (I) wherein thecompound has any one or more of the following features:

-   -   (I) R¹ is:        -   (i) 5-6 membered heteroaryl optionally substituted by 1-3            substituents selected from the group consisting of halogen,            cyano, hydroxyl, C₁—C₆ alkoxy,        -   C₃—C₆ cycloalkyl, and C₁—C₆ alkyl; or        -   (ii) 4-5 membered heterocyclyl optionally substituted by 1-3            substituents selected from the group consisting of halogen,            cyano, hydroxyl, C₁—C₆ alkoxy, C₃—C₆ cycloalkyl, C₁—C₆            alkyl, and oxo; or        -   (iii) R¹ —CONHR⁷, wherein R⁷ is H, C₃—C₆ cycloalkyl, or            C₁—C₆ alkyl;    -   (II) R² is:        -   (iv) C₁—C₆ alkyl optionally substituted by 1-3 substituents            selected from the group consisting of halogen, hydroxyl,            C₁—C₆ alkoxy, C₁—C₆ alkyl, C₃—C₆ cycloalkyl, 4- to            6-membered heterocyclyl, cyano, —C(O)NH(C₁—C₆ alkyl), and            —C(O)NH(C₃—C₆ cycloalkyl); or        -   (v) R² is C₃—C₆ cycloalkyl optionally substituted by 1-3            substituents selected from the group consisting of halogen,            hydroxyl, C₁—C₆ alkoxy, C₁—C₆ alkyl,        -   C₃—C₆ cycloalkyl, 4- to 6-membered heterocyclyl, cyano, oxo,            —C(O)NH(C₁—C₃ alkyl), and —C(O)NH(C₃—C₆ cycloalkyl); or        -   (vi) 4- to 6-membered heterocyclyl optionally substituted by            1-3 substituents selected from the group consisting of            halogen, hydroxyl, C₁—C₆ alkoxy,        -   C₁—C₆ alkyl, C₃—C₆ cycloalkyl, 4- to 6-membered            heterocyclyl, cyano, oxo, —C(O)NH(C₁—C₃ alkyl), and            —C(O)NH(C₃—C₆ cycloalkyl); or        -   (vii) H;    -   (III) R³ is:        -   (viii) H; or        -   (ix) C₁—C₆ alkyl optionally substituted by 1-3 substitutents            selected from the group consisting of halogen, hydroxyl, and            —O(C₁—C₆ alkyl); or        -   (x) —OR⁶, wherein R⁶ is C₁—C₆ alkyl; or        -   (xi) C₃—C₆ cycloalkyl optionally substituted by 1-3            substituents selected from the group consisting of halogen,            C₁—C₆ alkyl, and hydroxyl; or        -   (xii) 4- to 6-membered heterocyclyl optionally substituted            by 1-3 substituents selected from the group consisting of            halogen, C₁—C₆ alkyl, and hydroxyl;    -   (IV) R² and R³ together with the intervening atoms form ring A,        which is 5- to 6-membered heterocycloalkyl optionally        substituted by 1-3 substituents selected from the group        consisting of C₁—C₆ alkyl, hydroxyl, C₁—C₆ alkyl-OH, —C(O)(C₁—C₆        alkyl), and oxo;    -   (V) R⁴ is C₁—C₃ alkyl optionally substituted by 1-3 halogen;    -   (VI) L is —NH—CO—;    -   (VII) Z is CH, C-halo, or N;    -   (VIII) X is O.        In one variation, (I) applies. In one variation, (II) applies.        In one variation, (III) applies. In one variation, (IV) applies.        In one variation, (V) applies. In one variation, (VI) applies.        In one variation, (VII) applies. In one variation, (VIII)        applies. In one aspect of this variation, (I), (II), (III), (V),        (VI), (VII), and (VIII) apply. In another aspect of this        variation, (I), (IV), (V), (VI), (VII), and (VIII) apply. In one        variation, (V), (VI), (VII), and (VIII) apply. In one variation,        (i), (iv), and (viii) apply. In one variation, (i), (v),        and (viii) apply. In one variation, (iv), (iv), and (ix) apply.        In one variation, (iv), (iv), and (x) apply. In one variation,        (i), (v), and (ix) apply. In one variation, (i), (vi),        and (viii) apply. In one variation, (i), (iv), and (xi) apply.        In one variation, (i), (vii), and (viii) apply. In one        variation, (i), (iv), and (xii) apply. In one variation, (i)        and (IV) apply. In one variation, (ii), (iv), and (viii) apply.        In one variation, (ii) and (IV) apply. In one variation, (iii),        (iv), and (viii) apply. In one variation, (iii) and (IV) apply.

In one aspect, provided is a compound of formula (I) such as thoseprovided in the Examples (e.g., Examples 1-49) below and tabulated inTable 1 (Examples 50-232), or a tautomer or an N-oxide thereof, or anisotopomer of each thereof, or a prodrug of each of the above, or astereoisomer of the aforesaid, or a pharmaceutically acceptable salt ofeach of the foregoing, or a solvate of each of the preceding.

This disclosure also includes all salts, such as pharmaceuticallyacceptable salts, of compounds referred to herein. This disclosure alsoincludes any or all of the stereochemical forms, including anyenantiomeric or diastereomeric forms, and any tautomers or other forms,such as N-oxides, solvates, prodrugs, or isotopomers, of the compoundsdescribed. Unless stereochemistry is explicitly indicated in a chemicalstructure or name, the structure or name is intended to embrace allpossible stereoisomers of a compound depicted. In addition, where aspecific stereochemical form is depicted, it is understood that otherstereochemical forms are also embraced by the invention. All forms ofthe compounds are also embraced by the invention, such as crystalline ornon-crystalline forms of the compounds. Compositions comprising acompound of the invention are also intended, such as a composition ofsubstantially pure compound, including a specific stereochemical formthereof. Compositions comprising a mixture of compounds of the inventionin any ratio are also embraced by the invention, including mixtures oftwo or more stereochemical forms of a compound of the invention in anyratio, such that racemic, non- racemic, enantioenriched and scalemicmixtures of a compound are embraced.

In the descriptions herein, it is understood that every description,variation, embodiment, or aspect of a moiety can be combined with everydescription, variation, embodiment, or aspect of other moieties the sameas if each and every combination of descriptions is specifically andindividually listed. For example, every description, variation,embodiment, or aspect provided herein with respect to R¹ of formula (I)may be combined with every description, variation, embodiment, or aspectof R², R³, R⁴, R⁵, R⁶, R⁷, X, L, Y, and/or Z the same as if each andevery combination were specifically and individually listed. It is alsounderstood that all descriptions, variations, embodiments or aspects offormula (I), where applicable, apply equally to other formulae detailedherein, and are equally described, the same as if each and everydescription, variation, embodiment or aspect were separately andindividually listed for all formulae. For example, all descriptions,variations, embodiments, or aspects of formula (I), where applicable,apply equally to any of formulae (I-i), (Ia), (IA), (IA-1), (IIA),(IIB), (IIC), (IID), (IIE), (IIF), (IIG), (IIH), (Ib), (Ic), (Id), and(Ie) detailed herein, and are equally described, the same as if each andevery description, variation, embodiment or aspect were separately andindividually listed for all formulae.

The invention also includes all salts, such as pharmaceuticallyacceptable salts, of compounds referred to herein. The invention alsoincludes any or all of the stereochemical forms, including anyenantiomeric or diastereomeric forms, and any tautomers or other forms,such as N-oxides, solvates, prodrugs, or isotopomers, of the compoundsdescribed. Unless stereochemistry is explicitly indicated in a chemicalstructure or name, the structure or name is intended to embrace allpossible stereoisomers of a compound depicted. In addition, where aspecific stereochemical form is depicted, it is understood that otherstereochemical forms are also embraced by the invention. All forms ofthe compounds are also embraced by the invention, such as crystalline ornon-crystalline forms of the compounds. Compositions comprising acompound of the invention are also intended, such as a composition ofsubstantially pure compound, including a specific stereochemical formthereof. Compositions comprising a mixture of compounds of the inventionin any ratio are also embraced by the invention, including mixtures oftwo or more stereochemical forms of a compound of the invention in anyratio, such that racemic, non-racemic, enantioenriched and scalemicmixtures of a compound are embraced.

Pharmaceutical Compositions and Formulations

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this invention. Thus, the invention includes pharmaceuticalcompositions comprising a compound of the invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. In one aspect, the pharmaceuticallyacceptable salt is an acid addition salt, such as a salt formed with aninorganic or organic acid. Pharmaceutical compositions according to theinvention may take a form suitable for oral, buccal, parenteral, nasal,topical or rectal administration or a form suitable for administrationby inhalation.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form. In onevariation, “substantially pure” intends a composition that contains nomore than 35% impurity, wherein the impurity denotes a compound otherthan the compound comprising the majority of the composition or a saltthereof. For example, a composition of a substantially pure compoundselected from a compound of Table 1 (A, B, etc.) intends a compositionthat contains no more than 35% impurity, wherein the impurity denotes acompound other than the compound or a salt thereof. In one variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains no more than 25% impurity. In anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 20%impurity. In still another variation, a composition of substantiallypure compound or a salt thereof is provided wherein the compositioncontains or no more than 10% impurity. In a further variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains or no more than 5% impurity. In anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 3%impurity. In still another variation, a composition of substantiallypure compound or a salt thereof is provided wherein the compositioncontains or no more than 1% impurity. In a further variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains or no more than 0.5% impurity. In yetother variations, a composition of substantially pure compound meansthat the composition contains no more than 15% or preferably no morethan 10% or more preferably no more than 5% or even more preferably nomore than 3% and most preferably no more than 1% impurity, whichimpurity may be the compound in a different stereochemical form. Forinstance, and without limitation, a composition of substantially pure(S) compound means that the composition contains no more than 15% or nomore than 10% or no more than 5% or no more than 3% or no more than 1%of the (R) form of the compound.

In one variation, the compounds herein are synthetic compounds preparedfor administration to an individual such as a human. In anothervariation, compositions are provided containing a compound insubstantially pure form. In another variation, the invention embracespharmaceutical compositions comprising a compound detailed herein and apharmaceutically acceptable carrier or excipient. In another variation,methods of administering a compound are provided. The purified forms,pharmaceutical compositions and methods of administering the compoundsare suitable for any compound or form thereof detailed herein.

The compound may be formulated for any available delivery route,including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal orrectal), parenteral (e.g., intramuscular, subcutaneous or intravenous),topical or transdermal delivery form. A compound may be formulated withsuitable carriers to provide delivery forms that include, but are notlimited to, tablets, caplets, capsules (such as hard gelatin capsules orsoft elastic gelatin capsules), cachets, troches, lozenges, gums,dispersions, suppositories, ointments, cataplasms (poultices), pastes,powders, dressings, creams, solutions, patches, aerosols (e.g., nasalspray or inhalers), gels, suspensions (e.g., aqueous or non-aqueousliquid suspensions, oil-in-water emulsions or water-in-oil liquidemulsions), solutions and elixirs.

One or several compounds described herein can be used in the preparationof a formulation, such as a pharmaceutical formulation, by combining thecompound or compounds as an active ingredient with a pharmaceuticallyacceptable carrier, such as those mentioned above. Depending on thetherapeutic form of the system (e.g., transdermal patch vs. oraltablet), the carrier may be in various forms. In addition,pharmaceutical formulations may contain preservatives, solubilizers,stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters,and salts for the adjustment of osmotic pressure, buffers, coatingagents or antioxidants. Formulations comprising the compound may alsocontain other substances which have valuable therapeutic properties.Pharmaceutical formulations may be prepared by known pharmaceuticalmethods. Suitable formulations can be found, e.g., in Remington: TheScience and Practice of Pharmacy, Lippincott Williams & Wilkins, 21^(st)ed. (2005), which is incorporated herein by reference.

Compounds as described herein may be administered to individuals (e.g.,a human) in a form of generally accepted oral compositions, such astablets, coated tablets, and gel capsules in a hard or in soft shell,emulsions or suspensions. Examples of carriers, which may be used forthe preparation of such compositions, are lactose, corn starch or itsderivatives, talc, stearate or its salts, etc. Acceptable carriers forgel capsules with soft shell are, for instance, plant oils, wax, fats,semisolid and liquid polyols, and so on. In addition, pharmaceuticalformulations may contain preservatives, solubilizers, stabilizers,re-wetting agents, emulgators, sweeteners, dyes, adjusters, and saltsfor the adjustment of osmotic pressure, buffers, coating agents orantioxidants.

Any of the compounds described herein can be formulated in a tablet inany dosage form described.

Compositions comprising a compound provided herein are also described.In one variation, the composition comprises a compound and apharmaceutically acceptable carrier or excipient. In another variation,a composition of substantially pure compound is provided.

Methods of Use/Treatments

Compounds and compositions detailed herein, such as a pharmaceuticalcomposition containing a compound provided herein, or a salt thereof,and a pharmaceutically acceptable carrier or excipient, may be used inmethods of administration and treatment as provided herein. Thecompounds and compositions may also be used in in vitro methods, such asin vitro methods of administering a compound or composition to cells forscreening purposes and/or for conducting quality control assays.

In one aspect, provided herein is a method of inhibiting tyrosine kinaseenzymatic activity of a protein selected from Abelson protein (ABL1),Abelson-related protein (ABL2), or a chimeric protein BCR-ABL1,comprising contacting an effective amount of a compound or compositionprovided herein, to the protein. In one embodiment, provided herein is amethod of inhibiting tyrosine kinase enzymatic activity of Abelsonprotein (ABL1) comprising contacting an effective amount of a compoundor composition provided herein to ABL1. In another embodiment, providedherein is a method of inhibiting tyrosine kinase enzymatic activity ofAbelson-related protein (ABL2) comprising contacting an effective amountof a compound or composition provided herein to ABL2. In a furtherembodiment, provided herein is a method of inhibiting tyrosine kinaseenzymatic activity of a chimeric protein BCR-ABL1 comprising contactingan effective amount of a compound or composition provided herein to thechimeric protein.

In one aspect, provided herein is a method of treating a disease in apatient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound provided herein or a saltthereof, or a composition provided herein. In some embodiments, thecompound, or salt thereof, or the composition is administered accordingto a dosage described herein.

The compounds, or salts thereof, described herein and compositionsdescribed herein are believed to be effective for treating a variety ofdiseases and disorders. In some embodiments, a compound, or saltthereof, described herein or a composition described herein may be usedin a method of treating a disease mediated by ABL1, ABL2, and/orBCR-ABL1.

In one aspect, provided herein is a method of treating a disease,wherein modulation of BCR-ABL1 activity prevents, inhibits, orameliorates the pathology and/or symptomology of the disease, in apatient, comprising administering to the patient a therapeuticallyeffective amount of a compound or composition provided herein. In oneembodiment, provided herein is a method of treating a disease, whereinmodulation of BCR-ABL1 activity prevents the pathology and/orsymptomology of the disease, in a patient, comprising administering tothe patient a therapeutically effective amount of a compound orcomposition provided herein. In one embodiment, provided herein is amethod of treating a disease, wherein modulation of BCR-ABL1 activityinhibits the pathology and/or symptomology of the disease, in a patient,comprising administering to the patient a therapeutically effectiveamount of a compound or composition provided herein. In one embodiment,provided herein is a method of treating a disease, wherein modulation ofBCR-ABL1 activity ameliorates the pathology and/or symptomology of thedisease, in a patient, comprising administering to the patient atherapeutically effective amount of a compound or composition providedherein.

In some embodiments, the disease is leukemia. In some embodiments, theleukemia is chronic myeloid leukemia (CML), acute myeloid leukemia(AML), or acute lymphoblastic leukemia (ALL). In some embodiments, theleukemia is chronic myeloid leukemia (CML).

In one aspect, provided herein is a method of treating leukemia in apatient comprising administering to the patient a therapeuticallyeffective amount of a compound or composition provided herein. In oneaspect, provided herein is a method of treating leukemia in a patientcomprising administering to the patient a therapeutically effectiveamount of a compound or composition provided herein, wherein theleukemia is chronic myeloid leukemia (CML), acute myeloid leukemia(AML), or acute lymphoblastic leukemia (ALL).

In some embodiments, the leukemia treated herein is CML or ALL, and themethod further comprises administering a therapeutically effectiveamount of a compound selected from imatinib, nilotinib, dasatinib,bosutinib, ponatinib and bafetinib. In some embodiments, the leukemia isCML or ALL, and the method further comprises administering atherapeutically effective amount of a compound selected from imatinib,nilotinib, dasatinib, bosutinib, ponatinib and bafetinib.

In some embodiments, the leukemia is resistant to treatment. In someembodiments, the leukemia is resistant to treatment with imatinib,nilotinib, dasatinib, bosutinib, ponatinib, and/or bafetinib. In someembodiments, the CML is resistant to standard-of-care treatment such astreatment with one or more of imatinib, nilotinib, and dasatinib. Insome embodiments, the leukemia progressed during a prior treatment. Insome embodiments the prior treatment comprised administration ofimatinib, nilotinib, dasatinib, bosutinib, ponatinib, and/or bafetinib.

In some embodiments, the method further comprises administering atherapeutically effective amount of a compound selected from imatinib,nilotinib, dasatinib, bosutinib, ponatinib and bafetinib.

In some embodiments, the AML is secondary AML, which develops aftermyelodysplastic syndromes (MDS) or myeloproliferative neo-plasms (MPN).

In one aspect, provided herein is a method of treating a cancer in apatient comprising administering to the patient a therapeuticallyeffective amount of a compound or composition provided herein. In someembodiments, the cancer is melanoma, hereditary leiomyomatosis, renalcell carcinoma (HLRCC), or other solid tumors.

In one aspect, provided herein is a method of treating aneurodegenerative disease in a patient comprising administering to thepatient a therapeutically effective amount of a compound or compositionprovided herein. In some embodiments, the neurodegenerative disease isAlzheimer's or Parkinson's disease.

In another aspect is provided a method of delaying the onset and/ordevelopment of a disease or disorder that is mediated by BCR-ABL1activity in a patient (such as a human) who is at risk for developingthe disease or disorder. It is appreciated that delayed development mayencompass prevention in the event the individual or patient does notdevelop the disease or disorder. In one aspect, an individual or patientat risk of developing a disease or disorder that is mediated by BCR-ABL1activity has one or more risk factors for developing the disease ordisorder, such as a family history of an individual or patient havingthe disease or disorder, or having an underlying genetic condition thatis associated with an increased likelihood of developing the disease ordisorder.

In one aspect, provided herein is a method of delaying the onset and/ordevelopment of leukemia in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound or composition provided herein. In one variation, providedherein is a method of delaying the onset and/or development of CML in apatient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound or composition providedherein. In one variation, provided herein is a method of delaying theonset and/or development of AML in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound or composition provided herein. In one variation, providedherein is a method of delaying the onset and/or development of ALL in apatient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound or composition providedherein.

Methods of treating a disease mediated by BCR-ABL1, such as variousleukemias and the like, are well known to the skilled artisan and can beadapted to treating such a disease with a compound or compositionprovided herein.

In some embodiments, the patient is a mammal. In some embodiments, thepatient is a primate, dog, cat, rabbit, or rodent. In some embodiments,the patient is a primate. In some embodiments, the patient is a human.In some embodiments, the human is at least about or is about any of 18,21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments,the human is a child. In some embodiments, the human is less than aboutor about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 years old. In someembodiments, the patient has a genetic condition that is associated withan increased likelihood of developing the disease, such as the leukemia.In some embodiments, the patient has a mutation in the ABL1 and/or ABL2gene. In some embodiments, the patient is Philadelphia chromosomepositive.

A compound or composition provided herein may be administered to apatient in accordance with an effective dosing regimen for a desiredperiod of time or duration, such as at least about one month, at leastabout 2 months, at least about 3 months, at least about 6 months, or atleast about 12 months or longer, which in some variations may be for theduration of the patient's life. In one variation, the compound isadministered on a daily or intermittent schedule. The compound can beadministered to an patient continuously (for example, at least oncedaily) over a period of time. The dosing frequency can also be less thanonce daily, e.g., about a once weekly dosing. The dosing frequency canbe more than once daily, e.g., twice or three times daily. The dosingfrequency can also be intermittent (e.g., once daily dosing for 7 daysfollowed by no doses for 7 days, repeated for any 14 day time period,such as about 2 months, about 4 months, about 6 months or more). Any ofthe dosing frequencies can employ any of the compounds described hereintogether with any of the dosages described herein.

The compounds provided herein or a salt thereof may be administered to apatient via various routes, including, e.g., intravenous, intramuscular,subcutaneous, oral and transdermal.

The dose of a compound administered to a patient may vary with theparticular compound or salt thereof, the method of administration, andthe particular disease. In some embodiments, the amount of the compoundor salt thereof is a therapeutically effective amount.

The effective amount of the compound may in one aspect be a dose ofbetween about 0.01 and about 100 mg/kg. Effective amounts or doses ofthe compounds of the present disclosure may be ascertained by routinemethods, such as modeling, dose escalation, or clinical trials, takinginto account routine factors, e.g., the mode or route of administrationor drug delivery, the pharmacokinetics of the agent, the severity andcourse of the disease to be treated, the subject's health status,condition, and weight. An exemplary dose is in the range of about fromabout 0.7 mg to 7 g in a day, or about 7 mg to 350 mg in a day, or about350 mg to 1.75 gin a day, or about 1.75 to 7 g in a day.

Also provided herein are uses of a compound described herein or a saltthereof, or a composition described herein, in the manufacture of amedicament. In some embodiments, the manufacture of a medicament is forthe treatment of a disease described herein. In some embodiments, themanufacture of a medicament is for the treatment of a disease mediatedby ABL1, ABL2, and/or BCR-ABL1.

Articles of Manufacture and Kits

The present disclosure further provides articles of manufacturecomprising a compound described herein or a salt thereof, a compositiondescribed herein, or one or more unit dosages described herein insuitable packaging. In certain embodiments, the article of manufactureis for use in any of the methods described herein. Suitable packaging isknown in the art and includes, for example, vials, vessels, ampules,bottles, jars, flexible packaging and the like. An article ofmanufacture may further be sterilized and/or sealed.

The present disclosure further provides kits for carrying out themethods of the present disclosure, which comprises one or more compoundsdescribed herein or a composition comprising a compound describedherein. The kits may employ any of the compounds disclosed herein. Inone variation, the kit employs a compound described herein or a saltthereof. The kits may be used for any one or more of the uses describedherein, and, accordingly, may contain instructions for the treatment ofany disease or described herein, for example for the treatment ofcancer.

The kits may be in unit dosage forms, bulk packages (e.g., multi-dosepackages) or sub-unit doses. For example, kits may be provided thatcontain sufficient dosages of a compound as disclosed herein and/or anadditional pharmaceutically active compound useful for a diseasedetailed herein to provide effective treatment of a patient for anextended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9months, or more. Kits may also include multiple unit doses of thecompounds and instructions for use and be packaged in quantitiessufficient for storage and use in pharmacies (e.g., hospital pharmaciesand compounding pharmacies).

The kits may optionally include a set of instructions, generally writteninstructions, although electronic storage media (e.g., magnetic disketteor optical disk) containing instructions are also acceptable, relatingto the use of component(s) of the methods of the present disclosure. Theinstructions included with the kit generally include information as tothe components and their administration to a patient.

Exemplary Embodiments

The present disclosure is further described by the followingembodiments. The features of each of the embodiments are combinable withany of the other embodiments where appropriate and practical.

Embodiment 1. A compound of formula (I) or (Ia):

or a tautomer or an N-oxide thereof, or an isotopomer of each thereof,or a prodrug of each of the above, or a stereoisomer of the aforesaid,or a pharmaceutically acceptable salt of each of the foregoing, or asolvate of each of the preceding, wherein:

-   L is —NH—CO—, —CO—NH—, —NH—SO₂—, or —SO₂—NH—;-   R¹ is optionally substituted C₆—C₁₀ aryl, optionally substituted    5-10 membered heteroaryl, optionally substituted 4-10 membered    heterocycle, C(O)NR⁶R⁷, S(O)₂NR⁶R⁷, NR⁶COR⁷, or NR⁶SO₂R⁷, or    C(O)OR⁶;-   R² is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₂—C₆ alkenyl, optionally    substituted C₂—C₆ alkynyl, optionally substituted C₆—C₁₀ aryl, or    optionally substituted 5-10 membered heteroaryl;-   R³ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₂—C₆ alkenyl, optionally substituted C₂—C₆ alkynyl, optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl,    optionally substituted aryl, optionally substituted heteroaryl, OR⁶,    or NR⁶R⁷; or R² and R³ together with the intervening atoms form    cycloalkyl or heterocycloalkyl, preferably an optionally substituted    C₃—C₈ cycloalkyl or an optionally substituted 4-10 membered    heterocycloalkyl;-   R⁴ is optionally substituted C₁—C₆ alkyl, preferably C₁—C₃    haloalkyl, such as CF₃ or CF₂Cl, optionally substituted C₂—C₆    alkenyl, optionally substituted C₂—C₆ alkynyl;-   X is O or S;-   Y is CH, C—(C₁—C₂ alkyl), or C-halo or N;-   Z is CR⁵ or N;-   R⁵ is H or halogen when Z is CH;-   R⁶ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₆—C₁₀ aryl, or optionally    substituted 5-10 membered heteroaryl; and-   R⁷ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₆—C₁₀ aryl, or optionally    substituted 5-10 membered heteroaryl; or R⁶ and R⁷ together with the    nitrogen to which they are attached form an optionally substituted    4-7 membered heterocycle.

Embodiment 2. A compound of embodiment 1 of formula (IA):

wherein the variables are defined as in embodiment 1.

Embodiment 3. A compound of embodiment 2 selected from formula IIA-IIE:

-   wherein R¹⁰ is a 5-6 membered heteroaryl, preferably the heteroaryl    moiety has up to 2 ring nitrogen atoms;-   R²⁰ is optionally substituted C₁—C₃ alkyl or optionally substituted    C₃—C₄ cycloalkyl, preferably, R²⁰ is methyl, optionally substituted    isopropyl, or cyclopropyl;-   R³⁰ is H, optionally substituted C₁—C₃ alkyl or optionally    substituted C₃—C₄ cycloalkyl, preferably optionally substituted    cyclopropyl; and-   the remaining variables are defined as in embodiment 1.

Embodiment 4. The compound of embodiment 2 or 3, wherein X is O.

Embodiment 5. The compound of any one of embodiments 2-4, wherein R¹ is5-10 membered heteroaryl, preferably the heteroaryl moiety containing upto 2 ring nitrogen atoms, or R¹ is 4-10 membered heterocycle, preferablythe heterocyclyl moiety containing up to 2 ring nitrogen atoms.

Embodiment 6. The compound of any one embodiments 2-5, wherein R¹ is:

—CONH(cyclopropyl), —CONH₂, —CONHMe,

Embodiment 7. The compound of any one of embodiments 2-6, wherein R¹ ispyrimidinyl or pyrazolyl.

Embodiment 8. The compound of any one of embodiments 2-7, wherein R² isoptionally substituted C₁—C₃ alkyl or optionally substituted C₃—C₄cycloalkyl, preferably, R² is methyl, optionally substituted isopropyl,or cyclopropyl.

Embodiment 9. The compound of any one of embodiments 2-7, wherein R² is:methyl, isopropyl, tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl,tetrahydrofuranyl, tetrahydropyranyl,

Embodiment 10. The compound of any one embodiments 2-9, wherein R³ is:H, methyl, isopropyl, difluoromethyl, hydroxyethyl, cyclopropyl,cyclobutyl, —C(Me)₂OH, methoxymethyl, hydroxymethyl, methoxy,hydroxyethyl, —CH₂CH₂OH, or tetrahydropyranyl.

Embodment 11. The compound of any one of embodiments 2-6, wherein R² andR³ together form:

Embodiment 12. The compound of any one of embodiments 2-11, wherein R⁴is optionally substituted C₁—C₃ alkyl, preferably wherein the alkylgroup is substituted with one or more halo substituents, morepreferably, R⁴ is CF₃ or CF₂Cl.

Embodiment 13. The compound of any one of embodiments 2-12, wherein R⁵is H.

Embodiment 14. The compound of any one of embodiments 2-13, wherein Y isCH.

Embodiment 15. The compound of embodiment 1 of formula (Ib) or (Ic):

wherein the remaining variables are defined as in embodiment 1.

Embodiment 16. A compound selected from Compounds of formula (I) ofExamples 1-26 and from Table 1, or a tautomer or an N-oxide thereof, oran isotopomer of each thereof, or a prodrug of each of the above, or astereoisomer of the aforesaid, or a pharmaceutically acceptable salt ofeach of the foregoing, or a solvate of each of the preceding.

Embodiment 17. A composition comprising a compound of any one ofembodiments 2 to 16, and at least one pharmaceutically acceptableexcipient.

Embodiment 18. A method of inhibiting tyrosine kinase enzymatic activityof a protein selected from Abelson protein (ABL1), Abelson-relatedprotein (ABL2), or a chimeric protein BCR-ABL1, comprising contacting aneffective amount of a compound of any one of embodiments 2 to 16, or thecomposition of embodiment 17, to the protein.

Embodiment 19. A method of treating a disease, wherein modulation ofBCR-ABL1 activity prevents, inhibits, or ameliorates the pathologyand/or symptomology of the disease, in a patient, comprisingadministering to the patient a therapeutically effective amount of acompound of any one of embodiments 2 to 16, or the composition ofembodiment 17.

Embodiment 20. A method of treating leukemia in a patient comprisingadministering to the patient a therapeutically effective amount of thecompound of any one of embodiments 2 to 16, or the composition ofembodiment 17, wherein the leukemia is chronic myeloid leukemia (CML),acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

Embodiment 21. The method of embodiment 20, wherein the leukemia is CMLor ALL, and the method further comprising administering atherapeutically effective amount of a compound selected from imatinib,nilotinib, dasatinib, bosutinib, ponatinib and bafetinib.

Embodiment 22. The method of embodiment 20 or 21, wherein the CML isresistant to standard-of-care treatment such as treatment with one ormore of imatinib, nilotinib, and dasatinib.

Embodiment 23. The method of embodiment 20 or 21, wherein the AML issecondary AML, which develops after myelodysplastic syndromes (MDS) ormyeloproliferative neo-plasms (MPN).

Embodiment 24. A compound of formula (I) or (Ia):

or a tautomer thereof, or a pharmaceutically acceptable salt of any ofthe foregoing, wherein:

-   L is —NH—CO—, —CO—NH—, —NH—SO₂—, or —SO₂—NH—;-   R¹ is optionally substituted C₆—C₁₀ aryl, optionally substituted    5-10 membered heteroaryl, optionally substituted 4-10 membered    heterocycle, C(O)NR⁶R⁷, S(O)₂NR⁶R⁷, NR⁶COR⁷, NR⁶SO₂R⁷, or C(O)OR⁶;-   R² is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₂—C₆ alkenyl, optionally    substituted C₂—C₆ alkynyl, optionally substituted C₆—C₁₀ aryl, or    optionally substituted 5-10 membered heteroaryl;-   R³ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₂—C₆ alkenyl, optionally substituted C₂—C₆ alkynyl, optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl,    optionally substituted aryl, optionally substituted heteroaryl, OR⁶,    or NR⁶R⁷;-   or R² and R³ together with the intervening atoms form optionally    substituted C₃—C₈ cycloalkyl or optionally substituted 4-10 membered    heterocycloalkyl;

R⁴ is optionally substituted C₁—C₆ alkyl, optionally substituted C₂—C₆alkenyl, or optionally substituted C₂—C₆ alkynyl;

-   X is O or S;-   Y is CH, C—(C₁—C₂ alkyl), C-halo or N;-   Z is CR⁵ or N;-   R⁵ is H or halogen;-   R⁶ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₆—C₁₀ aryl, or optionally    substituted 5-10 membered heteroaryl; and-   R⁷ is H, optionally substituted C₁—C₆ alkyl, optionally substituted    C₃—C₈ cycloalkyl, optionally substituted 4-10 membered    heterocycloalkyl, optionally substituted C₆—C₁₀ aryl, or optionally    substituted 5-10 membered heteroaryl;-   or R⁶ and R⁷ together with the nitrogen to which they are attached    form an optionally substituted 4-7 membered heterocycle,-   provided that the compound is other than (i)    1H-Benzimidazole-7-carboxylic acid,    5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl- or (ii)    1H-Benzimidazole-7-carboxylic acid, 5-[[(4-ethoxy    phenyl)sulfonyl]amino]-1-methyl-.

Embodiment 25. The compound of embodiment 24, or a pharmaceuticallyacceptable salt thereof, wherein:

-   R¹ is C₆—C₁₀ aryl, 5-10 membered heteroaryl, or 4-10 membered    heterocycle, each of which is optionally substituted by 1-3    substituents selected from the group consisting of halogen, cyano,    hydroxyl, C₁—C₆ alkoxy, C₁—C₆ alkyl, and C₃—C₆ cycloalkyl;-   R² is C₁—C₆ alkyl, C₃—C₈ cycloalkyl, 4-10 membered heterocycloalkyl,    C₂—C₆ alkenyl, C₂—C₆ alkynyl, C₆—C₁₀ aryl, or 5-10 membered    heteroaryl, each of which is optionally substituted by 1-3    substituents selected from the group consisting of halogen,    hydroxyl, C₁—C₆ alkoxy, C₁—C₆ alkyl, C₃—C₆ cycloalkyl, 4- to    6-membered heterocyclyl, cyano, oxo, —C(O)NH(C₁—C₆ alkyl), and    —C(O)NH(C₃—C₆ cycloalkyl);-   R³ is C₁—C₆ alkyl, C₂—C₆ alkenyl, C₂—C₆ alkynyl, C₃—C₆ cycloalkyl,    4- to 6-membered heterocycloalkyl, C₆—Cio aryl, or 5- to 10-membered    heteroaryl, each of which is optionally substituted by 1-3    substituents selected from the group consisting of halogen,    hydroxyl, and C₁—C₆ alkyl; or R² and R³ together with the    intervening atoms form C₃—C₈ cycloalkyl or 4-10 membered    heterocycloalkyl, each of which is optionally substituted by 1-3    substituents selected from the group consisting of C₁—C₆ alkyl,    hydroxyl, C₁—C₆ alkyl-OH, —C(O)(C₁—C₆ alkyl), and oxo;-   R⁴ is C₁—C₆ alkyl, C₂—C₆ alkenyl, or C₂—C₆ alkynyl, each of which is    optionally substituted by 1-3 halogens;-   R⁶ is C₁—C₆ alkyl, C₃—C₈ cycloalkyl, 4-10 membered heterocycloalkyl,    C₆—Cto aryl, or 5-10 membered heteroaryl, each of which is    optionally substituted by 1-3 substituents selected from the group    consisting of halogen, hydroxyl, and C₁—C₆ alkyl; and is C₁—C₆    alkyl, C₃—C₈ cycloalkyl, 4-10 membered heterocycloalkyl, C₆—C₁₀    aryl, or 5-10 membered heteroaryl, each of which is optionally    substituted by 1-3 substituents selected from the group consisting    of halogen, hydroxyl, and C₁—C₆ alkyl;-   or R⁶ and R⁷ together with the nitrogen to which they are attached    form 4-7 membered heterocycle optionally substituted by 1-3    substituents selected from the group consisting of halogen,    hydroxyl, and C₁—C₆ alkyl.

Embodiment 26. The compound of embodiment 24 or 25, or apharmaceutically acceptable salt thereof, which is of formula (IA-1):

Embodiment 27. The compound of embodiment 26, or a pharmaceuticallyacceptable salt thereof, wherein the compound is selected from formula(IIA)-(IIH):

wherein:

-   R¹⁰ is an optionally substituted 5-6 membered heteroaryl;-   R²⁰ is optionally substituted C₁—C₃ alkyl, optionally substituted    C₃—C₄ cycloalkyl, or optionally substituted 4-6 membered    heterocycloalkyl;-   R³⁰ is H, optionally substituted C₁—C₃ alkyl, optionally substituted    C₃—C₄ cycloalkyl, or optionally substituted 5-6 membered    heterocycloalkyl; and-   Ring A is optionally substituted 5-6 membered heterocycloalkyl.

Embodiment 28. The compound of embodiment 27, or a pharmaceuticallyacceptable salt thereof, wherein:

-   R¹⁰ is 5-6 membered heteroaryl optionally substituted by 1-3    substituents selected from the group consisting of halogen, cyano,    hydroxyl, C₁—C₆ alkoxy, C₁—C₆ alkyl, and C₃—C₆ cycloalkyl;-   R²⁰ is C₁—C₃ alkyl, C₃—C₄ cycloalkyl, or 4-6 membered    heterocycloalkyl, each of which is optionally substituted by 1-3    substituents selected from the group consisting of halogen,    hydroxyl, C₁—C₆ alkoxy, C₁—C₆ alkyl, C₃—C₆ cycloalkyl, 4- to    6-membered heterocyclyl, cyano, oxo, —C(O)NH(C₁—C₆ alkyl), and    —C(O)NH(C₃—C₆ cycloalkyl);-   R³⁰ is C₁—C₃ alkyl, C₃—C₄ cycloalkyl, or 5-6 membered    heterocycloalkyl, each of which is optionally substituted by 1-3    substituents selected from the group consisting of halogen,    hydroxyl, and C₁—C₆ alkyl;-   Ring A is 5-6 membered heterocycloalkyl optionally substituted by    1-3 substituents selected from the group consisting of C₁—C₆ alkyl,    hydroxyl, C₁—C₆ alkyl-OH, —C(O)(Ci—C₆ alkyl), and oxo.

Embodiment 29. The compound of any one of embodiments 26-28, or apharmaceutically acceptable salt thereof, wherein:

-   X is O.

Embodiment 30. The compound of any one of embodiments 26-29, or apharmaceutically acceptable salt thereof, wherein:

-   R¹ is 5-10 membered heteroaryl or 4-10 membered heterocycle, each of    which is optionally substituted by 1-3 substituents selected from    the group consisting of halogen, cyano, hydroxyl, C₁—C₆ alkoxy,    C₁—C₆ alkyl, and C₃—C₆ cycloalkyl.

Embodiment 31. The compound of any one of embodiments 26-29, or apharmaceutically acceptable salt thereof, wherein:

-   R¹ is —CONH(cyclopropyl), —CONH₂, —CONHMe,

Embodiment 32. The compound of any one of embodiments 26-30, or apharmaceutically acceptable salt thereof, wherein:

-   R¹ is pyrimidinyl or pyrazolyl, each of which is optionally    substituted by 1-3 substituents selected from the group consisting    of halogen, cyano, hydroxyl, C₁—C₆ alkoxy, C₁—C₆ alkyl, and C₃—C₆    cycloalkyl.

Embodiment 33. The compound of any one of embodiments 26-32, or apharmaceutically acceptable salt thereof, wherein:

-   R² is C₁—C₃ alkyl or C₃—C₄ cycloalkyl, each of which is optionally    substituted by 1-3 substituents selected from the group consisting    of halogen, hydroxyl, C₁—C₆ alkoxy, C₁—C₆ alkyl, C₃—C₆ cycloalkyl,    4- to 6-membered heterocyclyl, cyano, oxo, —C(O)NH(C₁—C₆ alkyl), and    —C(O)NH(C₃—C₆ cycloalkyl).

Embodiment 34. The compound of any one of embodiments 26-32, or apharmaceutically acceptable salt thereof, wherein:

-   R² is methyl, ethyl, isopropyl, tertiary butyl, cyclopropyl,    cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl,

Embodiment 35. The compound of any one of embodiments 26-34, or apharmaceutically acceptable salt thereof, wherein:

-   R³ is H, methyl, isopropyl, difluoromethyl, hydroxyethyl,    cyclopropyl, cyclobutyl, —C(Me)₂OH, —CH(Me)OH, methoxymethyl,    hydroxymethyl, methoxy, ethoxy, —CH₂CH₂OH, or tetrahydropyranyl.

Embodiment 36. The compound of any one of embodiments 26-32, or apharmaceutically acceptable salt thereof, wherein R² and R³ togetherform:

Embodiment 37. The compound of any one of embodiments 26-36, or apharmaceutically acceptable salt thereof, wherein:

-   R⁴ is C₁—C₃ alkyl optionally substituted with 1-3 halo substituents.

Embodiment 38. The compound of any one of embodiments 26-37, or apharmaceutically acceptable salt thereof, wherein:

-   R⁴ is CF₃ or CF₂Cl.

Embodiment 39. The compound of any one of embodiments 26-38, or apharmaceutically acceptable salt thereof, wherein:

-   R⁵ is H.

Embodiment 40. The compound of any one of embodiments 26-39, or apharmaceutically acceptable salt thereof, wherein:

-   Y is CH.

Embodiment 41. The compound of embodiment 26, or a pharmaceuticallyacceptable salt thereof, which is of formula (Id) or (Ie):

Embodiment 42. A compound selected from Examples 1-232, or apharmaceutically acceptable salt thereof.

Embodiment 43. A composition comprising the compound of any one ofembodiments 26-42, or a pharmaceutically acceptable salt thereof, and atleast one pharmaceutically acceptable excipient.

Embodiment 44. A method of inhibiting tyrosine kinase enzymatic activityof a protein selected from the group consisting of Abelson protein(ABL1), Abelson-related protein (ABL2), and a chimeric protein BCR-ABL1,comprising contacting an effective amount of the compound of any one ofembodiments 26-42, or a pharmaceutically acceptable salt thereof, or thecomposition of embodiment 43, to the protein.

Embodiment 45. A method of treating a disease, wherein modulation ofBCR-ABL1 activity prevents, inhibits, or ameliorates the pathologyand/or symptomology of the disease, in a patient, comprisingadministering to the patient a therapeutically effective amount of thecompound of any one of embodiments 26-42, or a pharmaceuticallyacceptable salt thereof, or the composition of embodiment 43.

Embodiment 46. A method of treating leukemia in a patient comprisingadministering to the patient a therapeutically effective amount of thecompound of any one of embodiments 26-42, or a pharmaceuticallyacceptable salt thereof, or the composition of embodiment 43, whereinthe leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia(AML), or acute lymphoblastic leukemia (ALL).

Embodiment 47. The method of embodiment 46, wherein the leukemia is CMLor ALL, and the method further comprises administering a therapeuticallyeffective amount of a compound selected from the group consisting ofimatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib.

Embodiment 48. The method of embodiment 46 or 47, wherein the CML isresistant to standard-of-care treatment.

Embodiment 49. The method of embodiment 48, wherein the CML is resistantto treatment with one or more of imatinib, nilotinib, and dasatinib.

Embodiment 50. The method of embodiment 46, wherein the AML is secondaryAML, which develops after myelodysplastic syndromes (MDS) ormyeloproliferative neo-plasms (MPN).

EXAMPLES

The following abbreviations may be relevant for the application.

-   Abbreviations-   Ac: acetyl-   Bn: benzyl-   Bu: butyl-   Bz: benzoyl-   CMC: carboxymethyl cellulose-   DCM: dichloromethane-   DIPEA: diisopropylethylamine-   DMF: dimethylformamide-   DMEDA: N,N′-Dimethylethylenediamine-   DSC: N,N′-Disuccinimidyl carbonate or bis(2,5-dioxopyrrolidin-1-yl)    carbonate-   dppf: 1,1′-bis(diphenylphosphino)ferrocene-   Et: ethyl-   HATU:    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-blpyridinium    3-oxid hexafluorophosphate,-   NBS: N-bromosuccinimide-   PEG: polyethylene glycol-   PMB: paramethoxybenzyl-   Pr: propyl-   Py: pyridine-   rt: room temperature-   TEA: triethylamine-   TBDPS: tertiarybutyldiphenylsilyl-   TBAF: tetrabutylammonium fluoride-   THF: tetrahydrofuran-   TMS: trimethylsilyl-   TFA: trifluoroacetic acid-   Ts: tosyl-   Xphos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Synthetic Examples Preparing Compounds of Formula (I): Synthetic Schemes

As depicted in the Examples of Compounds of Formula (I), below, incertain exemplary embodiments, compounds of Formula (I) are preparedaccording to the following general procedures. It will be appreciatedthat, although the general methods depict the synthesis of certaincompounds of the present invention, the following general methods, andother methods known to one of ordinary skill in the art, can be appliedto all compounds and subclasses and species of each of these compounds,as described herein.

wherein R¹ and R² are as defined for the compound of formula (I).

Compounds of formula (S7) may be prepared by general synthetic methodsas shown in Scheme 1. Treatment of 1a with various primary amines (S1)in a suitable solvent such as ethanol with a base such as, but notlimited to, triethylamine at a temperature from about room temperatureto reflux and for a time varying from about 30 minutes to about 8 hours,can readily produce nitroaniline (S2). The phenylenediamine (S3) can beformed by reduction of nitroaniline (S2) using a reductant such as, butnot limited to, iron in a solvent such as, but not limited to aceticacid at a temperature from about room temperature to reflux and for atime varying from about 1 hour. The cyclization of phenylenediamine (S3)to benzimidazole (S4) can be carried out using a reagent such as, butnot limited to, trimethyl orthoformate in the presence of an acid suchas, but not limited to p-TsOH at a temperature from about roomtemperature to 100° C. and for a time varying from about 10 min to 1hour. Compounds of formula (S5) can be prepared from the bromide (S4)upon treatment with aryl, heteroaryl or heterocyclic boronic acids orboronate esters under palladium catalyst conditions such as, but notlimited to, [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II)in the presence of water and an inorganic base such as, but not limitedto, sodium carbonate, potassium carbonate, or potassium phosphate in anorganic solvent such as, but not limited to, 1,4-dioxane at an elevatedtemperature. Treatment of the ester (S5) with hydroxide sources such as,but not limited to, lithium hydroxide in the presence of water andorganic solvents such as, but not limited to, methanol and/ortetrahydrofuran yields carboxylic acid of formula (S6). Reaction ofcarboxylic acid (S6) with a coupling reagent such as, but not limitedto, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate, a base such as, but not limited to,diisopropylethylamine, and amine (1h) provides amide of formula (S7).

wherein R¹ and R² are as defined for the compound of formula (I); X ishalogen; and Z is CH or N.

Compounds of formula (S10) may be prepared by general synthetic methodsas shown in Scheme 2. Treatment of the ester (S5) with hydroxide sourcessuch as, but not limited to, lithium hydroxide in the presence of waterand organic solvents such as, but not limited to, methanol and/ortetrahydrofuran yields carboxylic acid of formula (S8). Reaction ofcarboxylic acid (S8) with a coupling reagent such as, but not limitedto, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate, a base such as, but not limited to,diisopropylethylamine, and amine (1h) provides amide of formula (S9).Compounds of formula (S10) can be prepared from the halide (S9) upontreatment with aryl, heteroaryl or heterocyclic boronic acids orboronate esters under palladium catalyst conditions such as, but notlimited to, [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II)in the presence of water and an inorganic base such as, but not limitedto, sodium carbonate, potassium carbonate, or potassium phosphate in anorganic solvent such as, but not limited to, 1,4-dioxane at an elevatedtemperature.

wherein R¹ and R³ are as defined for the compound of formula (I).

Compounds of formula (S15) may be prepared by general synthetic methodsas shown in Scheme 3. Compound (3a) can be treated with variouscarboxylic acids at a temperature from about 80° C. to 130° C. and for atime varying from about 1 hour to 2 hours to produce benzimidazoles offormula (S11). Treatment of benzimidazole (S11) with methyliodide in thepresence of a base such as, but not limited to, potassium carbonate inan organic solvent such as, but not limited to, N,N-dimethylformamide ata temperature at about 50° C. and for a time for about 3 hours toproduce benzimidazole (S12). Treatment of the ester (S12) with hydroxidesources such as, but not limited to, lithium hydroxide in the presenceof water and organic solvents such as, but not limited to, methanoland/or tetrahydrofuran yields carboxylic acid of formula (S13). Reactionof carboxylic acid (S13) with a coupling reagent such as, but notlimited to,[1-bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate, a base such as, but not limited to,diisopropylethylamine, and amine (1h) in an organic solvent such as, butnot limited to, N,N-dimethylformamide at about room temperature and fora time of about 30 minutes provides amide of formula (S14). Compounds offormula (S15) can be prepared from the bromide (S14) upon treatment witharyl, heteroaryl or heterocyclic boronic acids or boronate esters underpalladium catalyst conditions such as, but not limited to,[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) in thepresence of water and an inorganic base such as, but not limited to,sodium carbonate, potassium carbonate, or potassium phosphate in anorganic solvent such as, but not limited to, 1,4-dioxane at an elevatedtemperature.

wherein R¹, R², and R³ are as defined for the compound of formula (I).

Compounds of formula (S20) may be prepared by general synthetic methodsas shown in Scheme 4. Substituted phenylenediamines of formula (S16) canbe treated with various carboxylic acids at a temperature from about 80°C. to 130° C. and for a time varying from about 1 hour to 2 hours toproduce benzimidazoles of formula (S17). Treatment of the ester (S17)with hydroxide sources such as, but not limited to, lithium hydroxide inthe presence of water and organic solvents such as, but not limited to,methanol and/or tetrahydrofuran yields carboxylic acid of formula (S18).Reaction of carboxylic acid (S18) with a coupling reagent such as, butnot limited to,[1-bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate, a base such as, but not limited to,diisopropylethylamine, and amine (1h) in an organic solvent such as, butnot limited to, N,N-dimethylformamide at about room temperature and fora time of about 30 minutes provides amide of formula (S19). Compounds offormula (S20) can be prepared from the bromide (S19) upon treatment witharyl, heteroaryl or heterocyclic boronic acids or boronate esters underpalladium catalyst conditions such as, but not limited to,[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) in thepresence of water and an inorganic base such as, but not limited to,sodium carbonate, potassium carbonate, or potassium phosphate in anorganic solvent such as, but not limited to, 1,4-dioxane at an elevatedtemperature.

wherein R¹, R², and R³ are as defined for the compound of formula (I).

Compounds of formula (S26) may be prepared by general synthetic methodsas shown in Scheme 5. Treatment of the ester (S21) with hydroxidesources such as, but not limited to, lithium hydroxide in the presenceof water and organic solvents such as, but not limited to, methanoland/or tetrahydrofuran yields carboxylic acid of formula (S22). Reactionof carboxylic acid (S22) with a coupling reagent such as, but notlimited to, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate, a base such as, but not limited to,diisopropylethylamine, and amine (1h) in an organic solvent such as, butnot limited to, N,N-dimethylformamide at a temperature from roomtemperature to 50° C. and for a time of about 2 hours provides amide offormula (S23). The phenylenediamine (S24) can be formed by reductionnitroaniline (S23) using a reductant such as, but not limited to, ironin a solvent such as, but not limited to acetic acid at a temperaturefrom about 35° C. and for a time varying from about 3 hours. Substitutedphenylenediamines of formula (S24) can be treated with variouscarboxylic acids at a temperature from about 80° C. to 130° C. and for atime varying from about 1 hour to 2 hours to produce benzimidazoles offormula (S25). Compounds of formula (S26) can be prepared from thebromide (S25) upon treatment with aryl, heteroaryl or heterocyclicboronic acids or boronate esters under palladium catalyst conditionssuch as, but not limited to,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of water and an inorganic basesuch as, but not limited to, sodium carbonate, potassium carbonate, orpotassium phosphate in an organic solvent such as, but not limited to,1,4-dioxane at an elevated temperature.

wherein R¹, R², and R³ are as defined for the compound of formula (I).

Compounds of formula (S29) may be prepared by general synthetic methodsas shown in Scheme 6. Compounds of formula (S27) can be prepared fromthe bromide (S25) upon treatment with aryl, heteroaryl or heterocyclicboronic acids or boronate esters under palladium catalyst conditionssuch as, but not limited to, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the presence of water and an inorganic basesuch as, but not limited to, sodium carbonate, potassium carbonate, orpotassium phosphate in an organic solvent such as, but not limited to,1,4-dioxane at an elevated temperature. Treatment of the ester (S27)with hydroxide sources such as, but not limited to, lithium hydroxide inthe presence of water and organic solvents such as, but not limited to,methanol and/or tetrahydrofuran yields carboxylic acid of formula (S28).Reaction of carboxylic acid (S28) with a coupling reagent such as, butnot limited to,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate, a base such as, but not limited to,diisopropylethylamine, and amine (1h) in an organic solvent such as, butnot limited to, N,N-dimethylformamide at a temperature from roomtemperature to 50° C. and for a time of about 2 hours provides amide offormula (S29).

wherein R¹ is as defined for the compound of formula (I); X is a halide;and as used herein, R¹⁵ and R¹⁶ are optional substituents.

Compounds of formula (S38) may be prepared by general synthetic methodsas shown in Scheme 7. In the presence of an acid such as, but notlimited to, hydrochloric acid in an organic solvent such as, but notlimited to, ethyl acetate at a temperature at about 15° C. from a timeof about 2 hours, compounds of formula (S30) can be converted tocompounds of formula (S31). Treatment of amine (S31) with (la) in asuitable solvent such as ethanol with a base such as, but not limitedto, triethylamine at a temperature at about 15° C. and for a time ofabout 1 hour, can readily produce nitroaniline (S32). Thephenylenediamine (S33) can be formed by reduction nitroaniline (S32)using a reductant such as, but not limited to, iron in a solvent suchas, but not limited to acetic acid at a temperature from about roomtemperature to reflux and for a time varying from about 1 hour. Reactionof carboxylic acid (S33) with a coupling reagent such as, but notlimited to,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate, a base such as, but not limited to,diisopropylethylamine in an organic solvent such as, but not limited to,N,N-dimethylformamide at a temperature from about room temperature andfor a time of about 16 hours provides benzimidazole of formula (S34).Treatment of the ester (S34) with hydroxide sources such as, but notlimited to, lithium hydroxide in the presence of water and organicsolvents such as, but not limited to, methanol and/or tetrahydrofuranyields carboxylic acid of formula (S35). Reaction of carboxylic acid(S35) with a coupling reagent such as, but not limited to,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate, a base such as, but not limited to,pyridine, and amine (1h) in an organic solvent such as, but not limitedto, N,N-dimethylformamide at a temperature at about 40° C. and for atime of about 6 hours provides amide of formula (S36). Compounds offormula (S37) can be prepared from the bromide (S36) upon treatment witharyl, heteroaryl or heterocyclic boronic acids or boronate esters underpalladium catalyst conditions such as, but not limited to,[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) in thepresence of water and an inorganic base such as, but not limited to,sodium carbonate, potassium carbonate, or potassium phosphate in anorganic solvent such as, but not limited to, 1,4-dioxane at an elevatedtemperature. Alternatively, compounds of formula (S37) can be preparedby Stille coupling. Bromide (S36) is converted to stannane (S38) underunder palladium catalyst conditions such as, but not limited to,palladium tetrakis triphenylphosphine in an organic solvent such as, butnot limited to, toluene at an elevated temperature. Stannane (S38) canbe treated with various aryl or heteroaryl halides under under palladiumcatalyst conditions such as, but not limited to, palladium tetrakistriphenylphosphine in an organic solvent such as, but not limited to,DMSO at an elevated temperature.

wherein R¹ and R⁶ are as defined for the compound of formula (I).

Compounds of formula (S40) may be prepared by general synthetic methodsas shown in Scheme 8. Compound (S38) can be treated atetramethoxy-alkane at a temperature at about 50° C. and for a time ofabout 16 hours can afford compounds of formula (S39). Compounds offormula (S40) can be prepared from the bromide (S39) upon treatment witharyl, heteroaryl or heterocyclic boronic acids or boronate esters underpalladium catalyst conditions such as, but not limited to,[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) in thepresence of water and an inorganic base such as, but not limited to,sodium carbonate, potassium carbonate, or potassium phosphate in anorganic solvent such as, but not limited to, 1,4-dioxane at an elevatedtemperature.

wherein R¹ and R² are as defined for the compound of formula (1); andR¹⁵ and R¹⁶ are optional substituents.

Compounds of formula (S37 and S41) may be prepared by general syntheticmethods as shown in Scheme 9. Compound (S36) can be treated with variousaryl and heteroaryl stannanes under palladium catalyst conditions suchas, but not limited to, palladium tetrakis triphenylphosphine in anorganic solvent such as, but not limited to, toluene at an elevatedtemperature to afford compound (S37). Additionally, bromide (S36) can betreated with various amines under palladium catalyst or copperconditions such as, but not limited to,[(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate or (Bu₄NCuI₂)₂ in an organic solvent such as, but notlimited to, tetrahydrofuran or 1,4-dioxane at an elevated temperature toafford compounds of formula (S41).

wherein R¹ and R² are as defined for the compound of formula (I).

Compounds of formula (S46) may be prepared by general synthetic methodsas shown in Scheme 10. In the presence iron and acetic acid, compound(S42) can be cyclized to compounds of formula (S43). Treatment of theester (S43) with hydroxide sources such as, but not limited to, lithiumhydroxide in the presence of water and organic solvents such as, but notlimited to, methanol and/or tetrahydrofuran yields carboxylic acid offormula (S44). Reaction of carboxylic acid (S44) with a coupling reagentsuch as, but not limited to,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate, a base such as, but not limited to,pyridine, and amine (1h) in an organic solvent such as, but not limitedto, N,N-dimethylformamide at a temperature at about 40° C. and for atime of about 6 hours provides amide of formula (S45). Compounds offormula (S46) can be prepared from the bromide (S45) upon treatment witharyl, heteroaryl or heterocyclic boronic acids or boronate esters underpalladium catalyst conditions such as, but not limited to,[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) in thepresence of water and an inorganic base such as, but not limited to,sodium carbonate, potassium carbonate, or potassium phosphate in anorganic solvent such as, but not limited to, 1,4-dioxane at an elevatedtemperature.

Example 1 General Procedure AN-(4-(chlorodifluoromethoxy)phenyl)-1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

The title compound was prepared according to Scheme 1. This GeneralProcedure A exemplifies Scheme 1 and provides particular syntheticdetails as applied to the title compound.

Methyl 3-bromo-4-(methylamino)-5-nitrobenzoate (1c). To a solution ofmethyl 3-bromo-4-fluoro-5-nitro-benzoate (1a, 3 g, 10.79 mmol, 1 eq) andmethylamine hydrochloride (1b, 874.23 mg, 12.95 mmol, 1.2 eq) in EtOH(50 mL) was added TEA (3.28 g, 32.37 mmol, 4.51 mL, 3 eq). The mixturewas stirred at 15° C. for 12 hours. TLC (petroleum ether:ethylacetate=5:1, R_(f)=0.50) one major new spot with larger polarity wasdetected. The reaction mixture was concentrated under reduced pressure.The mixture was diluted with water and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give 1c as a yellowsolid. ¹H NMR (400 MHz, CDCl₃-d) δ 8.52 (d, J=2.0 Hz, 1H), 8.30 (d,J=2.0 Hz, 1H), 6.54 (br s, 1H), 3.91 (s, 3H), 3.09 (d, J=5.5 Hz, 3H).

Methyl 3-amino-5-bromo-4-(methylamino)benzoate (1d). To a solution ofmethyl 3-bromo-4-(methylamino)-5-nitrobenzoate (1c, 1.5 g, 5.19 mmol, 1eq) in AcOH (20 mL) at 15° C. was added Fe (2.90 g, 51.89 mmol, 10 eq)in one portion. The mixture was stirred at 15° C. for 1 hour. Anotherbatch of Fe (869.31 mg, 15.57 mmol, 3 eq) was added in one portion at15° C. and the mixture was stirred at 35° C. for 1 hour. TLC (petroleumether:ethyl acetate=3:1, R_(f)=0.30) indicated lc was consumedcompletely, and one major new spot with larger polarity was detected.Ethyl acetate (100 mL) was added. The organic layers were washed withH₂O (50 mL×2), saturated NaHCO₃ (30 mL×4) and brine (30 mL), and driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The productwas used in the next step without further purification. Compound ld wasobtained as a brown oil. ¹H NMR (400 MHz, CDCl₃-d) δ 7.63 (d, J=1.8 Hz,1H), 7.31 (d, J=1.8 Hz, 1H), 4.05-3.93 (m, 2H), 3.89-3.84 (m, 3H), 3.61(br s, 1H), 2.81-2.72 (m, 3H).

Methyl 7-bromo-1-methyl-1H-benzo[d]imidazole-5-carboxylate (1e). To asolution of methyl 3-amino-5-bromo-4-(methylamino)benzoate (1d, 0.1 g,0.386 mmol, 1 eq) in trimethoxymethane (15 mL) was addedp-TsOH (6.65 mg,0.039 mmol, 0.1 eq). The mixture was stirred at 100° C. for 1 hr. LCMSshowed ld was consumed completely and one main peak with desired masswas detected. The mixture was concentrated and ethyl acetate (20 mL) wasadded. The organic layers were washed with saturated NaHCO₃ (5 mL) andbrine (5 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to afford 1e as a white solid. The product was used in the nextstep without further purification. ¹1H NMR (400 MHz, CDCl₃-d) δ 8.43 (d,J=1.5 Hz, 1H), 8.16 (d, J=1.3 Hz, 1H), 7.91 (s, 1H), 4.18 (s, 3H),4.00-3.92 (m, 3H).

Methyl 1-methyl-7-(pyrimidin-5-yl)-1H-benzo [d]imidazole-5-carboxylate(1F). To a mixture of methyl 7-bromo-1-methyl-1H-benzo[d]imidazole-5-carboxylate (1e, 0.1 g, 0.372 mmol, 1 eq) andpyrimidin-5-ylboronic acid (92.09 mg, 0.743 mmol, 2 eq) in dioxane (5mL) and H₂O (0.3 mL) under N₂ was added Pd(dppf)Cl₂ (19.03 mg, 0.026mmol, 0.07 eq), Na₂CO₃ (78.77 mg, 0.743 mmol, 2 eq). The mixture wasstirred at 100° C. for 12 hours. LCMS showed le remained and one mainpeak with desired mass was detected. The mixture was filtered andconcentrated to give the crude residue. The residue was purified byprep-TLC (SiO₂, ethyl acetate:methanol=9:1). Compound if was obtained asa brown solid. ¹H NMR (400 MHz, CDCl₃-d) δ 9.35 (s, 1H), 8.90 (s, 2H),8.62 (d, J=1.5 Hz, 1H), 7.97-7.88 (m, 2H), 3.98 (s, 3H), 3.51 (s, 3H).

1-Methyl-7-(pyrimidin-5-yl)-1H-benzo [d]imidazole-5-carboxylic acid(1g). To a solution of methyl1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylate (1f,0.045 g, 0.168 mmol, 1 eq) in THF (2 mL), MeOH (2 mL) and H₂O (1 mL) at15° C. under N₂ was added LiOH.H₂O (14.08 mg, 0.335 mmol, 2 eq). Themixture was stirred at 15° C. for 12 hours. LCMS showed if was consumedcompletely and one main peak with desired mass was detected. The mixturewas adjusted to pH=5 with aqueous HCl (1M) and concentrated to give thecrude product ig as a brown solid. The product was used into the nextstep without further purification.

N-(4-(chlorodifluoromethoxy)phenyl)-1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide(1). To a solution of1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid (1g,0.04 g, 0.157 mmol, 1 eq) and 4-(chlorodifluoromethoxy)aniline (33.50mg, 0.173 mmol, 1.1 eq), HATU (71.79 mg, 0.189 mmol, 1.2 eq) in DMF (1mL) at 15° C. was added DIEA (61.00 mg, 0.472 mmol, 82.21 uL, 3 eq). Themixture was stirred at 15° C. for 12 hours. LCMS showed ig was consumedcompletely and desired mass was detected. The mixture was concentrated,and the resulting residue was purified by prep-HPLC (FA condition,column: Luna C18 100*30 5u; mobile phase: [water (0.225% FA)-ACN]; B %:35%-50%, 14 min) to afford the title compound 1 as a yellow solid. ¹HNMR (400 MHz, MeOD-d₄) δ ¹N NMR (400 MHz, MeOD-d₄) δ 9.31 (s, 1H), 9.06(s, 2H), 8.45 (d, J=1.5 Hz, 1H), 8.39 (s, 1H), 7.91 (d, J=1.5 Hz, 1H),7.84 (d, J=9.0 Hz, 2H), 7.31 (d, J=9.0 Hz, 2H), 3.60 (s, 3H).

Example 2 General Procedure BN-(4-(chlorodifluoromethoxy)phenyl)-1-(1s,3s)-3-hydroxycyclobutyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

The title compound was prepared according to Scheme 2. This GeneralProcedure B exemplifies Scheme 2 and provides particular syntheticdetails as applied to the title compound.

7-Bromo-1-(1s,3s)-3-hydroxycyclobutyl)-1H-benzo[d]midazole-5-carboxylicacid (2b). To a solution of methyl7-bromo-1-(1s,3s)-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-5-carboxylate(synthesized in a similar fashion to le; 2a, 140 mg, 0.431 mmol, 1 eq)in THF (2 mL), MeOH (2 mL) and H₂O (1 mL) was added LiOH.H₂O (27.10 mg,0.646 mmol, 1.5 eq). The mixture was stirred at 15° C. for 12 hr. LCMSshowed 2a was consumed completely and desired MS was detected. Theaqueous phase was acidified to pH=5 with the addition of aqueous HCl.The mixture was filtered and concentrated in vacuo and compound 2bobtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (br s, 1H)8.72 (s, 1H) 8.19 (d, J=1.1 Hz, 1H) 7.96 (s, 1H) 5.37 (br d, J=6.2 Hz,1H) 4.94-5.07 (m, 1H) 4.01-4.11 (m, 1H) 2.86-2.95 (m, 2H) 2.37-2.44 (m,2H).

7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(1s,3s)-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-5-carboxamide (2c) To a solution of7-bromo-1-((1s,3s)-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-5-carboxylicacid (2b, 100 mg, 0.321 mmol, 1 eq) and4-[chloro(difluoro)methoxy]aniline (74.66 mg, 0.386 mmol, 1.2 eq) in DMF(2 mL) was added HATU (146.65 mg, 0.386 mmol, 1.2 eq) and DIEA (83.08mg, 0.643 mmol, 111.97 uL, 2 eq). The mixture was stirred at 15° C. for12 hr. LCMS showed 2b was consumed completely and desired MS wasdetected. The mixture was diluted with water (3 mL) and extracted withEtOAc (10 mL×3). The combined organic layers were washed with brine (3mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The residue was purified by prep-TLC (SiO₂, ethylacetate:methanol=10:1) to give 2c as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ10.48 (s, 1H) 8.72 (s, 1H) 8.40 (d, J=1.3 Hz, 1H) 8.05 (d,J=1.3 Hz, 1H) 7.92 (d, J=9.0 Hz, 2H) 7.36 (d, J=9.0 Hz, 2H) 5.37 (d,J=6.4 Hz, 1H) 4.96-5.08 (m, 1H) 4.01-4.13 (m, 1H) 2.89-2.98 (m, 2H)2.36-2.43 (m, 2H).

N-(4-(chlorodifluoromethoxy)phenyl)-1-((1s,3s)-3-hydroxycyclobutyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide(2). To a solution of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(1s,3s)-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-5-carboxamide (2c, 40 mg, 0.082 mmol, 1 eq) andpyrimidin-5-ylboronic acid (20.37 mg, 0.164 mmol, 2 eq) in dioxane (3mL) and H₂O (0.3 mL) was added Pd(dppf)Cl₂ (6.01 mg, 8.22 umol, 0.1 eq)and K₃PO₄ (52.34 mg, 0.247 mmol, 3 eq). The mixture was stirred at 100°C. for 12 hr. LCMS showed 2c was consumed completely and desired MS wasdetected. The aqueous phase was extracted with H₂O (5 mL) and ethylacetate (5 mL×3). The combined organic layers were washed with brine (5mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The mixture purified by prep-HPLC (NH₄HCO₃ condition, column: WatersXbridge Prep OBD C18 150*30 10u; mobile phase: [water (10 mMNH₄HCO₃)-ACN]; B %: 25%-45%,10 min) to give the title compound 2 as awhite solid. MS mass calculated for [M-H]⁺ (C₂₃H₁₈O₃N₅ClF₂) requires m/z486.1, LCMS found m/z 486.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1H)9.36 (s, 1H) 9.06 (s, 2H) 8.62 (s, 1H) 8.51 (d, J=1.5 Hz, 1H) 7.94 (d,J=9.0 Hz, 2H) 7.81 (d, J=1.5 Hz, 1H) 7.37 (d, J=8.8 Hz, 2H) 5.21 (d,J=6.6 Hz, 1H) 3.97 (quin, J=8.0 Hz, 1H) 3.66 (sxt, J=7.1 Hz, 1H)2.06-2.16 (m, 4H).

Example 3 General Procedure CN-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-methyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxamide

The title compound was prepared according to Scheme 3. This GeneralProcedure C exemplifies Scheme 3 and provides particular syntheticdetails as applied to the title compound.

Methyl 4-bromo-2-(difluoromethyl)-1H-benzo[d]imidazole-6-carboxylate(3b). Methyl 3,4-diamino-5-bromobenzoate (synthesized in a similarfashion to 1d; 3a, 0.2 g, 0.816 mmol, 1 eq) was dissolved in CHF₂COOH (3mL)), the mixture was stirred at 130° C. for 1 hr. TLC (petroleumether:ethyl acetate=3:1) showed the starting material was consumed andLCMS showed the desired MS. The mixture was concentrated, and theresidue was dissolved in EtOAc (10 ml). The organic layers were washedwith aq. NaHCO₃ (5 mL×3) and then concentrated to afford 3b as a brownsolid. The crude product was used in the next step without furtherpurification.

Methyl4-bromo-2-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylate(3c). To a solution of methyl4-bromo-2-(difluoromethyl)-1H-benzo[d]imidazole-6-carboxylate (3b, 200mg, 0.656 mmol, 1 eq) in DMF(2 mL) was added K₂CO₃ (271.82 mg, 1.97mmol, 3 eq) and MeI (930.52 mg, 6.56 mmol, 408.12 uL, 10 eq). Themixture was stirred at 50° C. for 10 hr. TLC (petroleum ether:ethylacetate=2:1) showed the starting material was consumed. The mixture wasconcentrated and the residue was purified by prep-TLC (SiO₂, petroleumether:ethyl acetate=2:1) to afford 3c as a yellow solid. ¹H NMR (400MHz, CDCl₃-d) δ 8.24 (d, J=1.1 Hz, 1H), 8.17 (d, J=1.1 Hz, 1H),7.17-6.85 (m, 1H), 4.04 (s, 3H), 3.98 (s, 3H).

4-Bromo-2-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylicacid (3d). To a solution of methyl4-bromo-2-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylate(3c, 115 mg, 0.36 mmol, 1 eq) in THF (3 mL), MeOH (2 mL) and H₂O (1 mL)at 25° C. was added LiOH.H₂O (30.24 mg, 0.721 mmol, 2 eq). The mixturewas stirred at 50° C. for 2 hr. TLC (petroleum ether:ethyl acetate=2:1)showed the starting material was consumed. The mixture was concentratedand aq. HCl (1M) was added until pH=3-4. The suspension was filtered,and the solid was washed with H₂O (1 mL) and dried to give 3d as ayellow solid. The crude product was used in the next step withoutfurther purification. ¹H NMR (400 MHz, MeOD-d₄) δ 8.35 (s, 1H), 8.07 (s,1H), 7.70-7.32 (m, 1H), 4.02 (s, 3H).

4-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxamide(3e). To a solution of4-bromo-2-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylicacid (3d, 110 mg, 0.361 mmol, 1 eq) in DMF(3 mL) was added DIPEA (93.20mg, 0.721 mmol, 125.61 uL, 3 eq) and HATU (205.65 mg, 0.541 mmol, 1.2eq). The mixture was stirred at 25° C. for 0.5 hr before4-(chlorodifluoromethoxy)aniline (1h, 83.76 mg, 0.433 mmol, 1.2 eq) wasadded. The reaction mixture was stirred at 25° C. for 3.5 hrs. TLC(petroleum ether:ethyl acetate=3:1) showed the starting material wasconsumed and LCMS showed desired MS. The mixture was concentrated andthe residue was purified by column chromatography by prep-TLC (SiO₂,petroleum ether:ethyl acetate=1:1) to afford 3e as a yellow solid. ¹HNMR (400 MHz, CDCl₃-d) δ 8.10 (d, J=1.2 Hz, 1H), 7.98-7.91 (m, 2H), 7.74(d, J=8.9 Hz, 2H), 7.30 (d, J=8.9 Hz, 2H), 7.18-6.88 (m, 1H), 4.07 (s,3H).

N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-methyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxamide(3). To a solution of4-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxamide(3e, 100 mg, 0.208 mmol, 1 eq) and pyrimidin-5-ylboronic acid (51.56 mg,0.416 mmol, 2 eq) in dioxane (4 mL) and H₂O (1 mL) under N₂ was addedK₃PO₄ (132.49 mg, 0.624 mmol, 3 eq) and Pd(dppf)Cl₂ (15.22 mg, 0.021mmol, 0.1 eq). The mixture was stirred under N₂ at 100° C. for 4 hrs.LCMS showed the starting material was consumed and desired product wasdetected. The mixture was poured into water and extracted with EtOAc.The organic layers were concentrated and the resulting residue waspurified by prep-HPLC (NH₄HCO₃ condition, column: Waters Xbridge PrepOBD C18 150*30 10 u; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %:30%-50%,10 min) to give the title compound 3 as a white solid. MS masscalculated for [M+H]⁺ (C₂₁H₁₄ClF₄N₅O₂) requires m/z 480.1, LCMS foundm/z 480.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H), 9.55 (s, 2H), 9.26(s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 7.93 (d, J=9.2 Hz, 2H), 7.69-7.37(m, 3H), 4.08 (s, 3H).

Example 4N-(4-(chlorodifluoromethoxy)phenyl)-1,2-dimethyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxamide

Methyl 7-bromo-2-methyl-1H-benzo[d]imidazole-5-carboxylate (4a). To amixture of Methyl 3,4-diamino-5-bromobenzoate (synthesized in a similarfashion to 1d; 3a, 0.16 g, 0.653 mmol, 1 eq) in CH₃COOH (3 mL) at 20° C.was added 4-methylbenzenesulfonic acid (11.24 mg, 0.065 mmol, 0.1 eq).The mixture was stirred at 100° C. for 3 hours. LCMS showed desired MS.The mixture was poured into water (20 mL), and then was extracted withEtOAC (20 mL×3). The combined organic layers were dried with anhydrousNa₂SO₄, filtered and concentrated in vacuo to give 4a as a brown oil.

Methyl 4-bromo-1,2-dimethyl-1H-benzo[d]imidazole-6-carboxylate (4b). Toa mixture of Methyl 7-bromo-2-methyl-1H-benzo[d]imidazole-5-carboxylate(4a, 0.15 g, 0.557 mmol, 1 eq) and NaH (44.59 mg, 1.11 mmol, 60% purity,2 eq) in DMF (1 mL) was added CH₃I (158.24 mg, 1.11 mmol, 69.40 uL, 2eq). The mixture was stirred at 15° C. for 16 hours. LCMS showed desiredMS. The mixture was poured into water (20 mL), and then was extractedwith EtOAC (20 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give theproduct. The residue was purified by prep-TLC (Petroleum ether:Ethylacetate=0:1, R_(f)=0.40) to give 4b as a brown oil.

Methyl1,2-dimethyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxylate (4c).To a mixture of methyl4-bromo-1,2-dimethyl-1H-benzo[d]imidazole-6-carboxylate (4b, 0.02 g,0.071 mmol, 1 eq), pyrimidin-5-yl-boronic acid (26.26 mg, 0.212 mmol, 3eq) and K₃PO₄ (44.98 mg, 0.212 mmol, 3 eq) in dioxane (2 mL), H₂O (0.2mL) under N₂ was added Pd(dppf)Cl₂ (5.17 mg, 7.06 umol, 0.1 eq). Themixture was stirred at 110° C. for 16 hours. LCMS showed desired MS. Themixture was poured into water and extracted with EtOAc. The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the crude product. The residue waspurified by prep-TLC (petroleum ether:ethyl acetate=0:1, R_(f)=0.37) toafford 4c as yellow oil.

1,2-Dimethyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxylic acid(4d). To a mixture of 4c (0.015 g, 0.053 mmol, 1 eq) in H₂O (0.5 mL),THF (1 mL), MeOH (1 mL) was added LiOH.H₂O (4.46 mg, 0.106 mmol, 2 eq).The mixture was stirred at 15° C. for 16 hours. LCMS showed the desireMS. The mixture was poured into water and extracted with EtOAc, thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the 4d as red solid. The crude product wasused in the next step without further purification.

N-(4-(chlorodifluoromethoxy)phenyl)-1,2-dimethyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxamide(4). To a mixture of1,2-dimethyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxylic acid(4d, 15 mg, 0.056 mmol, 1 eq) and HATU (25.51 mg, 0.067 mmol, 1.2 eq),DIPEA (14.45 mg, 0.112 mmol, 19.48 uL, 2 eq) in DMF (1 mL) at 20° C. wasadded 4-[chloro(difluoro)methoxy]aniline (1h, 16.24 mg, 0.084 mmol, 1.5eq). The mixture was stirred at 20° C. for 16 hours. The mixture wasconcentrated in vacuo. LCMS showed desired MS. The mixture was pouredinto water and extracted with EtOAc, and the combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo togive the crude product. The residue was purified by prep-HPLC (TFAcondition, column: Nano-Micro UniSil 5-100 C18 ULTRA 100*250 mm 5 um;mobile phase: [water (0.1%TFA)-ACN]; B %: 25%-50%, 11 min) to afford thetitle compound 4 as a white solid. MS mass calculated for [M+H]⁺(C₂₁H₁₆ClF₂N₅O₂) requires m/z 444.1, LCMS found m/z 444.1. ¹H NMR (400MHz, MeOD-d₄) δ 9.33-9.25 (m, 3H), 8.48 (s, 1H), 8.25 (s, 1H), 7.88 (d,J=9.0 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 4.07 (s, 3H), 2.85 (s, 3H).

Example 5 General Procedure D(R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

The title compound was prepared according to Scheme 4. This GeneralProcedure D exemplifies Scheme 4 and provides particular syntheticdetails as applied to the title compound.

(R)-methyl7-bromo-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxylate(5b). A solution of (R)-methyl3-amino-5-bromo-4-(1-hydroxypropan-2-yl)amino)benzoate (synthesized in asimilar fashion to 1d; 5a, 230 mg, 0.759 mmol, 1 eq) in2,2-difluoroacetic acid (4.59 g, 0.048 mmol, 3 mL, 63 eq) was stirred at110° C. for 3 hr. LCMS showed 5a was consumed completely and desired MSwas detected. The mixture was filtered and concentrated under reducedpressure to give the crude residue. The residue was purified by prep-TLC(SiO₂, petroleum ether:ethyl acetate=0:1) to provide 5b as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 1H) 8.11 (s, 1H), 7.37-7.75(m, 1H), 5.95-6.10 (m, 1H), 5.31 (t, J=5.2 Hz, 1H), 3.90 (s, 3H),3.74-3.87 (m, 2H), 1.59 (br d, J=7.3 Hz, 3H).

(R)-7-bromo-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxylicacid (5c). To a solution of (R)-methyl7-bromo-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxylate(5b, 130 mg, 0.358 mmol, 1 eq) in THF (1 mL), MeOH (1 mL) and H₂O (0.5mL) was added LiOH.H₂O (30.04 mg, 0.716 mmol, 2 eq). The mixture wasstirred at 15° C. for 2 hr. LCMS showed 5b was consumed completely anddesired MS was detected. The aqueous phase was acidified to pH=5 withaqueous HCl. The mixture was filtered and concentrated in vacuo. Theproduct was used in the next step without further purification. Compound5c was obtained as a white solid.

(R)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxamide (5e). To a solution of(R)-7-bromo-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxylicacid (5c, 100 mg, 0.286 mmol, 1 eq) and 4-(chlorodifluoromethoxy)aniline(1h, 66.54 mg, 0.344 mmol, 1.2 eq) in DMF (2 mL) was added HATU (130.69mg, 0.344 mmol, 1.2 eq) and DIEA (148.08 mg, 1.15 mmol, 199.56 uL, 4eq). The mixture was stirred at 15° C. for 12 hr. LCMS showed 5c wasconsumed completely and desired MS was detected. The mixture was dilutedwith water (5 mL) and extracted with EtOAc (10 mL×3). The combinedorganic layers were washed with brine (5 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the cruderesidue. The residue was purified by prep-TLC (SiO₂, ethylacetate:methanol=10:1) to afford 5e as a yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ 10.56 (s, 1H), 8.49 (s, 1H), 8.21 (s, 1H), 7.93 (d, J=9.3 Hz,2H), 7.43-7.71 (m, 1H), 7.38 (br d, J=9.0 Hz, 2H), 6.02 (br d, J=6.2 Hz,1H), 5.23-5.45 (m, 1H), 3.72-3.93 (m, 2H), 1.60 (br d, J=6.8 Hz, 3H).

(R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide(5). To a solution of(R)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-hydroxypropan-2-yl)-1H-benzo[d]imidazole-5-carboxamide(5e, 60 mg, 0.114 mmol, 1 eq) and pyrimidin-5-ylboronic acid (28.34 mg,0.229 mmol, 2 eq) in dioxane (1 mL) and H₂O (0.1 mL) was addedPd(dppf)Cl₂ (8.37 mg, 11.44 umol, 0.1 eq) and K₃PO₄ (72.82 mg, 0.343mmol, 3 eq). The mixture was stirred at 100° C. for 16 hr. LCMS showed5e was consumed completely and desired MS was detected. The mixture wasfiltered and concentrated under reduced pressure to give the cruderesidue. The residue was purified by prep-TLC (SiO₂, ethylacetate:methanol=10:1) to afford title compound 5 as a white solid. MSmass calculated for [M+H]⁺ (C₂₃H₁₈O₃N₅ClF₄) requires m/z 524.1, LCMSfound m/z 524.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H) 9.35 (s, 1H)9.07 (s, 2H) 8.58 (d, J=1.5 Hz, 1H) 7.93 (d, J=9.3 Hz, 2H) 7.84 (d,J=1.8 Hz, 1H) 7.42-7.70 (m, 1H) 7.38 (d, J=9.0 Hz, 2H) 5.11 (t, J=5.1Hz, 1H) 4.25-4.45 (m, 1H) 3.41-3.63 (m, 2H) 1.37 (br d, J=7.1 Hz, 3 H).

Example 6 General Procedure EN-(4-(chlorodifluoromethoxy)phenyl)-2-isopropyl-1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

The title compound was prepared according to Scheme 5. This GeneralProcedure E exemplifies Scheme 5 and provides particular syntheticdetails as applied to the title compound.

3-Bromo-4-(methylamino)-5-nitrobenzoic acid (6a). To a mixture of methyl3-bromo-4-(methylamino)-5-nitrobenzoate (1c, 1.7 g, 5.88 mmol, 1 eq) inTHF (20 mL) and H₂O (4 mL) was added LiOH.H₂O (493.55 mg, 11.76 mmol, 2eq) in one portion. The mixture was stirred at 60° C. for 12 hours. TLC(petroleum ether:ethyl acetate=3:1, R_(f)=0.0) indicated lc was consumedcompletely, and one major new spot with larger polarity was detected.The mixture was adjusted to pH=3 with aqueous HCl (1M). The mixture wasfiltered, and the yellow solid was washed with H₂O (10 mL) to give 6b asa yellow solid. The product was used in the next step without furtherpurification.

3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)-5-nitrobenzamide(6b) To a mixture of 3-bromo-4-(methylamino)-5-nitrobenzoic acid (6a,1.27 g, 6.54 mmol, 1.2 eq) and 4-(chlorodifluoromethoxy)aniline (1h,1.50 g, 5.45 mmol, 1 eq) in DMF (10 mL) was added HATU (2.28 g, 6.00mmol, 1.1 eq) and DIEA (775.28 mg, 6.00 mmol, 1.04 mL, 1.1 eq) in oneportion. The mixture was heated to 30° C. and stirred for 12 hours.LC-MS showed one main peak with desired mass was detected. The mixturewas concentrated and the resulting residue was purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=20:1 to 5:1) toyield 6b as a yellow solid.

3-Amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)benzamide(6c). A solution of3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)-5-nitrobenzamide(6b, 2.1 g, 4.66 mmol, 1 eq) in AcOH (15 mL) at 20° C. was added Fe(2.60 g, 46.60 mmol, 10 eq) in one portion. The mixture was stirred at35° C. for 3 h. TLC (petroleum ether:ethyl acetate=1:1, R_(f)=0.6)indicated 6b was consumed completely and one new spot formed. Ethylacetate (40 mL) was added and the mixture was filtered through a Celite®pad. The filtrate was washed with H₂O (30 mL), saturated NaHCO₃ solution(20 mL×3), and brine (20 mL) before being dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to afford 6c as a yellow solid. Thecrude product was used in the next step without further purification.

3-Amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)benzamide(6d). A mixture of3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)benzamide(6c, 0.075 g, 0.178 mmol, 1 eq) in 2-methylpropanoic acid (314.18 mg,3.57 mmol, 330.72 uL, 20 eq) was stirred at 130° C. for 12 hours. Themixture turned from brown to dark. LC-MS showed 6e was consumedcompletely and desired mass was detected. The residue was purified byprep-TLC (SiO₂, petroleum ether:ethyl acetate=1:1) to afford 6d as ayellow oil.

N-(4-(chlorodifluoromethoxy)phenyl)-2-isopropyl-1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide(6). To a mixture of3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)benzamide(6d,0.03 g, 0.063 mmol, 1 eq) and pyrimidin-5-ylboronic acid (15.73 mg,0.127 mmol, 2 eq) in dioxane (4 mL) and H₂O (0.3 mL) at 15° C. under N₂was added Pd(dppf)Cl₂ (4.64 mg, 6.35 umol, 0.1 eq), K₃PO₄ (40.41 mg,0.190 mmol, 3 eq) in one portion. The mixture was stirred at 110° C. for12 hours. LC-MS showed the starting material was consumed completely andone main peak with desired mass was detected. The mixture was filteredthrough a Celite® pad and the filtrate was concentrated to give a cruderesidue. The residue was purified by prep-HPLC (TFA condition: column:Luna C18 100*30 5 u; mobile phase: [water (0.1% TFA)-ACN]; B %: 15%-45%,14 min) to provide the title compound 6 as a white solid. MS masscalculated for [M+H]⁺ (C₂₃H₂₀O₂N₅ClF₂) requires m/z 472.1, LCMS foundm/z 472.1. ¹H NMR (400 MHz, MeOD-d₄) δ 9.34 (s, 1H), 9.07 (s, 2H), 8.43(d, J=1.5 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.84 (d, J=9.0 Hz, 2H), 7.31(d, J=9.0 Hz, 2H), 3.64-3.55 (m, 4H), 1.52 (d, J=6.8 Hz, 6H).

Example 7 General Procedure F

N-(4-(chlorodifluoromethoxy)phenyl)-1,2-dimethyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

The title compound was prepared according to Scheme 6. This GeneralProcedure F exemplifies Scheme 6 and provides particular syntheticdetails as applied to the title compound.

Methyl1,2-dimethyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylate (7b).To a mixture of methyl 7-bromo-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxylate (synthesized in a similar fashion to 1e; 7a,0.15 g, 0.53 mmol, 1 eq) and pyrimidin-5-ylboronic acid (65.65 mg, 0.53mmol, 1 eq) in dioxane (5 mL) and H₂O (0.5 mL) under N₂ was addedPd(dppf)Cl₂ (38.77 mg, 0.53 mmol, 0.1 eq) and K₃PO₄.3H₂O (423.28 mg,1.59 mmol, 3 eq). The mixture was stirred at 110° C. for 16 hours. TLC(ethyl acetate:methanol=8:1, R_(f)=0.20) indicated 7a was consumedcompletely, and one major new spot with larger polarity was detected.LC-MS showed 7a was consumed completely and one main peak with desiredmass was detected. The mixture was filtered and concentrated to give aresidue that was purified by prep-TLC (SiO₂, ethyl acetate:methanol=8:1)to afford 7b as a light brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.30(s, 1H), 9.01 (s, 2H), 8.21 (d, J=1.3 Hz, 1H), 7.67 (d, J=1.3 Hz, 1H),3.87 (s, 3H), 3.32-3.31 (m, 3H), 2.55 (s, 3H).

1,2-Dimethyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid(7c). To a solution of methyl1,2-dimethyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylate (7b,0.06 g, 0.213 mmol, 1 eq) in THF (2 mL), MeOH (2 mL), H₂O (1 mL) wasadded LiOH.H₂O (17.84 mg, 0.425 mmol, 2 eq). The mixture was stirred at50° C. for 3 hours. LC-MS showed 7b was consumed completely and one mainpeak with desired mass was detected. The mixture was adjusted to pH=5with HCl aqueous (1M) and concentrated to give 7c as a brown solid. Theproduct was used in the next step without further purification.

N-(4-(chlorodifluoromethoxy)phenyl)-1,2-dimethyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide(7) To a mixture of1,2-dimethyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid(7c, 0.057 g, 0.212 mmol, 1 eq) and 4-(chlorodifluoromethoxy)aniline(1h, 45.24 mg, 0.234 mmol, 1.1 eq), HATU (96.95 mg, 0.255 mmol, 1.2 eq)in DMF (2 mL) was added DIEA (82.38 mg, 0.637 mmol, 111.03 uL, 3 eq).The mixture was stirred at 15° C. for 12 hours. LC-MS showed 7c wasconsumed completely and one main peak with desired mass was detected.The mixture was concentrated to give a crude residue that was purifiedby prep-HPLC (FA condition: column: Nano-micro Kromasil C18 100*30 mm 5um; mobile phase: [water (0.225% FA)-ACN]; B %: 1%-50%, 15 min) to yieldthe title compound 7 as a white solid. MS mass calculated for [M+H]⁺(C₂₁H₁₆ClF₂N₅O₂) requires m/z 444.1, LCMS found m/z 444.2. ¹H NMR (400MHz, DMSO-d₆) 6 10.42 (s, 1H), 9.32 (s, 1H), 9.06 (s, 2H), 8.35 (d,J=1.3 Hz, 1H), 7.92 (d, J=9.0 Hz, 2H), 7.76 (d, J=1.5 Hz, 1H), 7.36 (d,J=9.0 Hz, 2H), 3.37 (s, 3H), 2.57 (s, 3H).

Example 8 General Procedure GN-[4-[chloro(difluoro)methoxy]phenyl]-6-pyrimidin-5-yl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxamide

The title compound was prepared according to Scheme 7. This GeneralProcedure G exemplifies Scheme 7 and provides particular syntheticdetails as applied to the title compound.

2-(2-Aminoethoxy)acetic acid (8b). A solution of2-[2-(tert-butoxycarbonylamino)ethoxy]acetic acid (8a, 800 mg, 3.65mmol, 1 eq) in HCl/EtOAc (5 mL) was stirred at 15° C. for 2 hr. LCMSshowed 8) was consumed completely and desired MS was detected. Themixture was filtered and concentrated under reduced pressure to give 8bas a white solid. The product was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (br s, 1H) 8.09 (br s,3H) 4.06 (s, 2H) 3.66 (t, J=5.2 Hz, 2H) 2.87-3.02 (m, 2H).

2-[2-(2-Bromo-4-methoxycarbonyl-6-nitro-anilino)ethoxy]acetic acid (8c).To a solution of methyl 3-bromo-4-fluoro-5-nitrobenzoate (1a, 500 mg,1.80 mmol, 1 eq) and 2-(2-aminoethoxy)acetic acid (8b, 335.75 mg, 2.16mmol, 1.2 eq, HCl) in EtOH (10 mL) was added TEA (454.94 mg, 4.50 mmol,625.78 uL, 2.5 eq). The mixture was stirred at 15° C. for 1 hr. LCMSshowed la was consumed completely and desired MS was detected. Thereaction mixture was concentrated under reduced pressure. The mixturewas diluted with water (25 mL) and extracted with EtOAc (20 mL×3). Thecombined organic layers were washed with brine (15 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thecrude residue. The residue was purified by silica gel chromatography(column height: 250 mm, diameter: 100 mm, 200-300 mesh silica gel,petroleum ether/ethyl acetate=5/1, ethyl acetate/methanol/CH₃COOH=5/1/0.1%) to afford 8c as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.28 (d, J=1.7 Hz, 1H) 8.18 (d, J=1.7 Hz, 1H) 7.09 (brs, 1H) 3.89 (s, 2H) 3.83 (s, 3H) 3.65 (br t, J=5.0 Hz, 2H) 3.19-3.28 (m,2H).

2-[2-(2-Amino-6-bromo-4-methoxycarbonyl-anilino)ethoxy]acetic acid (8d).To a solution of2-[2-(2-bromo-4-methoxycarbonyl-6-nitro-anilino)ethoxylacetic acid (8c,420 mg, 1.11 mmol, 1 eq) in AcOH (5 mL) was added Fe (621.91 mg, 11.14mmol, 10 eq). The reaction mixture was stirred at 35° C. for 1 hr. LCMSshowed 8c was consumed completely and desired MS was detected. Themixture was filtered through a Celite® pad and washed with ethylacetate. The mixture was concentrated under reduced pressure to give thecrude residue that was purified by prep-HPLC (HCl condition, column:Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water (0.05%HCl)-ACN]; B %: 15%-45%,10 min) to give 8d as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 7.53 (s, 1H) 7.49 (s, 1H) 4.16 (br s, 2H) 4.05 (s,3H) 3.60 (br t, J=4.9 Hz, 2H) 3.26-3.35 (m, 2H).

Methyl6-bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxylate(8e). To a solution of2-[2-(2-amino-6-bromo-4-methoxycarbonyl-anilino)ethoxy]acetic acid (8d,100 mg, 0.261 mmol, 1 eq, HCl) in DMF (20 mL) was added HATU (109.03 mg,0.287 mmol, 1.1 eq) and DIEA (101.07 mg, 0.782 mmol, 136.21 uL, 3 eq).The mixture was stirred at 20° C. for 16 hr. LCMS showed 8d was consumedcompletely and desired MS was detected. The mixture was diluted withwater (5 mL) and extracted with EtOAc (5 mL×3). The combined organiclayers were washed with brine (5 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude residue. Theresidue was purified by prep-TLC (SiO₂, petroleum ether:ethylacetate=0:1) to afford 8e as a white solid. ¹H NMR (400 MHz, CDCl₃-d) δ8.34 (d, J=1.3 Hz, 1H) 8.11 (d, J=1.3 Hz, 1H) 5.05 (s, 2H) 4.71 (t,J=5.3 Hz, 2H) 4.15-4.26 (m, 2H) 3.95 (s, 3H).

6-Bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxylicacid (8f). To a solution of Methyl6-bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxylate(8e, 50 mg, 0.161 mmol, 1 eq) in MeOH (1 mL), THF (1 mL) and H₂O (0.5mL) was added LiOH.H₂O (13.49 mg, 0.321 mmol, 2 eq). The mixture wasstirred at 40° C. for 6 hr. TLC (petroleum ether:ethyl acetate=0:1,R_(f)=0) showed 8e was consumed completely and one major new spot withmore polarity was detected. The mixture was concentrated in vacuo. Themixture was added to H₂O (3 mL) and the aqueous phase was acidified topH=5 with aqueous HC_(1.) The mixture was concentrated in vacuo toafford 8f as a white solid. The product was used in the next stepwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) 6 8.13 (d, J=1.2Hz, 1H) 7.94 (d, J=1.3 Hz, 1H) 5.00 (s, 2H) 4.63 (t, J=5.3 Hz, 2H) 4.16(t, J=5.3 Hz, 2H).

6-Bromo-N-[4-[chloro(difluoro)methoxy]phenyl]-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxamide(8g). To a solution of6-bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxylicacid (8f, 45 mg, 0.151 mmol, 1 eq) and 4-(chlorodifluoromethoxy)aniline(1h, 35.18 mg, 0.182 mmol, 1.2 eq) in pyridine (2 mL) was added HATU(69.11 mg, 0.182 mmol, 1.2 eq). The mixture was stirred at 40° C. for 6hr. LCMS showed 8f was consumed completely and desired MS was detected.The mixture was diluted with water (5 mL) and extracted with EtOAc (5mL×3). The combined organic layers were washed with brine (5 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe crude residue. The residue was purified by prep-TLC (SiO₂, petroleumether:ethyl acetate=0:1) to obtain 8g as a white solid. ¹H NMR (400 MHz,CDCl₃-d) δ 8.11 (s, 1H) 8.00 (s, 1H) 7.96 (br s, 1H) 7.73 (d, J=8.9 Hz,2H) 7.29 (br s, 2H) 5.06 (s, 2H) 4.73 (t, J=5.3 Hz, 2H) 4.22 (t, J=5.1Hz, 2H).

N-[4-[chloro(difluoro)methoxy]phenyl]-6-pyrimidin-5-yl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxamide(8). To a solution of6-bromo-N-[4-[chloro(difluoro)methoxy]phenyl]-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-8-carboxamide(8 g, 40 mg, 0.085 mmol, 1 eq) and pyrimidin-5-ylboronic acid (20.97 mg,0.169 mmol, 2 eq) in dioxane (1 mL) and H₂O (0.1 mL) was addedPd(dppf)Cl₂ (6.19 mg, 8.46 umol, 0.1 eq) and K₃PO₄ (53.89 mg, 0.254mmol, 3 eq). The mixture was stirred at 110° C. for 16 hr. LCMS showed8g was consumed completely and desired MS was detected. The mixture wasdiluted with water (15 mL) and extracted with EtOAc (15 mL×3). Thecombined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thecrude residue. The residue was purified by prep-TLC (SiO₂, ethylacetate:methanol=10:1) to afford the title compound 8 as a yellow solid.MS mass calculated for [M+H]⁺ (C₂₂H₁₆O₃N₅ClF₂) requires m/z 472.1, LCMSfound m/z 472.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1H) 9.32 (s, 1H)9.10 (s, 2H) 8.42 (s, 1H) 7.93 (d, J=9.0 Hz, 2H) 7.82 (s, 1H) 7.26-7.45(m, 1H) 7.36 (br d, J=8.8 Hz, 1H) 5.03 (s, 2H) 3.98 (br t, J=4.9 Hz, 2H)3.70-3.83 (m, 2H).

Example 9 General Procedure HN-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-2-methoxy-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

The title compound was prepared according to Scheme 8. This GeneralProcedure H exemplifies Scheme 8 and provides particular syntheticdetails as applied to the title compound.

7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-2-methoxy-1H-benzo[d]imidazole-5-carboxamide(9b). To a solution of3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(isopropylamino)benzamide(synthesized in a similar fashion to 6c; 9a, 100 mg, 0.223 mmol, 1 eq)in AcOH (2 mL) was added tetramethoxymethane (197.23 mg, 1.45 mmol, 6.5eq). The mixture was stirred at 50° C. for 16 hr. LCMS showed 9a wasconsumed completely and desired MS was detected. TLC (petroleumether:ethyl acetate=3:1, R_(f)=0.4) showed 9a was consumed completely,one major new spot with less polarity was detected. The reaction mixturewas concentrated under reduced pressure. The mixture was washed withsaturated aqueous NaHCO₃, dried over Na₂SO₄ and evaporated to dryness.The crude residue was purified by prep-TLC (SiO₂, petroleum ether:ethylacetate=3:1) to afford 9b as a white solid.

N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-2-methoxy-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (9). A mixture of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-2-methoxy-1H-benzo[d]imidazole-5-carboxamide (9b, 40 mg, 0.082 mmol, 1 eq),pyrimidin-5-ylboronic acid (30.42 mg, 0.246 mmol, 3 eq), Pd (dppf) Cl₂(5.99 mg, 8.18 umol, 0.1 eq) and K₃PO₄ (52.12 mg, 0.246 mmol, 3 eq) indioxane (4 mL) and H₂O (0.4 mL) was degassed and purged with N₂ 3 times.The mixture was stirred at 110° C. for 16 hr under N₂ atmosphere. LCMSshowed 9b was consumed completely and desired MS was detected. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by prep-TLC (SiO₂, petroleum ether:ethyl acetate=1:1) toyield the title compound 9 as a white solid. MS mass calculated for[M+1]⁺ (C₂₃H₂₀ClF₂N₅O₃) requires m/z 488.1, LCMS found m/z 488.0. ¹H NMR(400 MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.33 (s, 1H), 9.06 (s, 2H), 8.21 (d,J=1.5 Hz, 1H), 7.94-7.89 (m, 2H), 7.64 (d, J=1.5 Hz, 1H), 7.35 (d, J=9.0Hz, 2H), 4.18 (s, 3H), 3.99-3.91 (m, 1H), 1.29 (d, J=6.8 Hz, 6H).

Example 10N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyclopropyl-1H-imidazol-1-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide

N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyclopropyl-1H-imidazol-1-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(10). A mixture of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (synthesized in a similar fashion to 2c; 10a,50 mg, 0.109 mmol, 1 eq), 4-cyclopropyl-1H-imidazole (10b, 23.58 mg,0.218 mmol, 2 eq), CuI (20.76 mg, 0.109 mmol, 1 eq), K₂CO₃ (150.65 mg,1.09 mmol, 10 eq) and DMEDA (19.22 mg, 0.218 mmol, 23.47 μL, 2 eq) inDMF (2 mL) was degassed and purged with N₂ 3 times before the mixturewas stirred at 140° C. for 16 hr under N₂ atmosphere. The reactionmixture was concentrated, and the aqueous phase was extracted with ethylacetate (30 mL). The combined organic layers were washed with brine (5mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The crude product was purified by prep-TLC (ethyl acetate:methanol=10:1, R_(f)=0.2) to give the crude product, which was furtherpurified by prep-HPLC (NH₄HCO₃, column: Waters Xbridge Prep OBD C18150*30 10 u; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %:35%-55%,10min) to give title compound 10 as a white solid. MS masscalculated for [M+1]⁺ (C₂₄H₂₂ClF₂N₅O₂) requires m/z 486.1, LCMS foundm/z 486.1; ¹H NMR (400 MHz, MeOD-d₄) 6 8.61 (s, 1H), 8.49 (d, J=1.5 Hz,1H), 7.92 (s, 2H), 7.87-7.81 (m, 2H), 7.33-7.24 (m, 3H), 3.78 (td,J=6.7, 13.4 Hz, 1H), 2.01-1.89 (m, 1H), 1.46 (br s, 6H), 0.93 (dd,J=2.0, 8.4 Hz, 2H), 0.77 (br s, 2H).

Example 11N-(4-(chlorodifluoromethoxy)phenyl)-7-(1H-imidazol-1-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide

N-(4-(chlorodifluoromethoxy)phenyl)-7-(1H-imidazol-1-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(11). To a solution of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (10a, 200 mg, 0.436 mmol, 1 eq) and imidazole(148.42 mg, 2.18 mmol, 5 eq) in DMF (2 mL) was added K₂CO₃ (602.64 mg,4.36 mmol, 10 eq), CuI (83.04 mg, 0.436 mmol, 1 eq) and DMEDA (115.31mg, 1.31 mmol, 140.79 uL, 3 eq). The mixture was stirred at 120° C. for12 hrs. The mixture was dissolved in EtOAc (20 ml), washed with water(10 mL×5) and the organic layers were concentrated. The residue waspurified by prep-HPLC (NH₄HCO₃ condition, column: Waters Xbridge PrepOBD C18 150*30 10 u; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %:35%-55%,10 min) to give title compound 11 as a white solid. MS masscalculated for [M+1]⁺ (C₂₁H₁₈ClF₂N₅O₂) requires m/z 446.1, LCMS foundm/z 446.1; ¹H NMR (400 MHz, MeOD-d₄) δ 8.63 (s, 1H), 8.51 (d, J=1.5 Hz,1H), 8.11 (s, 1H), 7.95 (d, J=1.5 Hz, 1H), 7.89-7.78 (m, 2H), 7.58 (d,J=1.3 Hz, 1H), 7.35-7.21 (m, 3H), 3.70 (quin, J=6.7 Hz, 1H), 1.43 (br s,6H).

Example 12N-(4-(chlorodifluoromethoxy)phenyl)-2-(2-hydroxyethyl)-1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

Methyl3-((3-bromo-5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(methylamino)phenyl)amino)-3-oxopropanoate(12a). To a solution of3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(methylamino)benzamide(6c, 300 mg, 0.713 mmol) and methyl 3-chloro-3-oxo-propanoate (107.11mg, 0.784 mmol, 83.68 uL, 1.1 eq) in DCM was added TEA (72.17 mg, 0.713mmol, 99.27 uL, 1 eq) drop-wise. The mixture was warmed to 30° C. andstirred for 0.5 hr. The reaction mixture was concentrated under reducedpressure to remove solvent. The residue was purified by prep-TLC (SiO₂,petroleum ether:ethyl acetate=1: 1) to give 12a as a brown solid.

Methyl2-(7-bromo-5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-1-methyl-1H-benzo[d]imidazol-2-ypacetate (12b). A solution of methyl3-(3-bromo-5-(4-(chlorodifluoromethoxy)phenyl)carbamoyl)-2-(methylamino)phenyl)amino)-3-oxopropanoate(12a, 130 mg, 0.25 mmol) in AcOH was heated to 60° C. and stirred for 6hours. LC-MS showed reactant was consumed completely and one main peakwith desired mass was detected. The mixture was poured into EtOAc andthe mixture was washed with water, saturated NaHCO₃ and brine. Thecombined organic layers were dried over Na₂SO₄ and concentrated. Theresidue was purified by prep-TLC to give 12b as a yellow solid.

7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide(12c). To a solution of methyl2-(7-bromo-5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-1-methyl-1H-benzo[d]imidazol-2-yl)acetate (12b, 50 mg, 0.099 mmol, 1 eq) in THF at 20° C.was added LiBH₄ (10.83 mg, 0.497 mmol, 5 eq) slowly in one portion underN₂. The mixture was heated to 30° C. and stirred for 50 min. LC-MSshowed reactant was consumed completely and one main peak with desiredmass was detected. After the reaction mixture was cooled to 0° C., thereaction mixture was quenched by addition of H₂O, and acidified with 1NHCl to pH=6. The reaction mixture was concentrated under reducedpressure to remove solvent. The residue was purified by prep-TLC (SiO₂,ethyl acetate:methanol=10: 1) to give 12c as a yellow solid.

N-(4-(chlorodifluoromethoxy)phenyl)-2-(2-hydroxyethyl)-1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (12). To a mixture of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide (12c, 40 mg, 0.084 mmol, 1 eq) andpyrimidin-5-ylboronic acid (12e, 20.88 mg, 0.169 mmol, 2 eq) in dioxane(3 mL) and H₂O (0.3 mL) at 20° C. under N₂ was added Pd(dppf)Cl₂ (6.17mg, 8.43 umol, 0.1 eq) and K₃PO₄ (53.66 mg, 0.253 mmol, 3 eq) in oneportion. The mixture was heated to 110° C. and stirred for 12 hours.LC-MS showed reactant was consumed completely and one main peak withdesired mass was detected. The mixture was filtered through a Celite®pad, and the filtrate was concentrated to give crude product, which waspurified by prep-HPLC (FA condition, column: Waters Atlantis T3 150*30*5um; mobile phase: [water (0.225% FA)-ACN]; B %: 10%-50%,13 min) toafford the title compound 12 as a white solid. MS mass calculated for[M+1]⁺ (C₂₂H₁₈ClF₂N₅O₃) requires m/z 474.1, LCMS found m/z 474.0; ¹H NMR(400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 9.33 (s, 1H), 9.07 (s, 2H), 8.40 (s,1H), 7.94 (d, J=9.2 Hz, 2H), 7.77 (s, 1H), 7.37 (d, J=9.0 Hz, 2H), 4.89(t, J=5.6 Hz, 1H), 3.96-3.86 (m, 2H), 3.41 (s, 3H), 3.07 (t, J=6.9 Hz,2H).

Example 13N⁵-(4-(chlorodifluoromethoxy)phenyl)-N⁷-cyclopropyl-1-isopropyl-1H-benzo[d]imidazole-5,7-dicarboxamide

Methyl5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-1-isopropyl-1H-benzo[d]imidazole-7-carboxylate(13b). To a mixture of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (10a, 200 mg, 0.436 mmol, 1 eq) and TEA(176.49 mg, 1.74 mmol, 242.76 uL, 4 eq) in MeOH (20 mL) at 20° C. underNa was added Pd(PPh₃)₄ (50.39 mg, 0.044 mmol, 0.1 eq) in one portion.The mixture was heated to 100° C. and stirred for 24 hours under CO(0.436 mmol, 3 MPa). LC-MS showed ˜60% of reactant remained. One newpeak was observed by LC-MS and ˜30% of the desired compound wasdetected. HPLC showed 60% of reactant remained. The mixture was filteredthrough a Celite® pad, and the filtrate was concentrated to give crudeproduct. The residue was purified by prep-HPLC (NH₄HCO3, column:YMC-Actus Triart C_(18 100*30) mm*5 um; mobile phase: [water (10 mMNH4HCO3)-ACN]; B %: 45%-65%, 12 min) to give 13b as a white solid. ¹HNMR (400 MHz, MeOD-d₄) δ 8.64 (s, 1H), 8.54 (d, J=1.7 Hz, 1H), 8.45 (d,J=1.7 Hz, 1H), 7.90-7.84 (m, 2H), 7.33 (d, J=9.0 Hz, 2H), 5.40 (td,J=6.6, 13.3 Hz, 1H), 4.06 (s, 3H), 1.62 (d, J=6.7 Hz, 6H).

5-((4-(Chlorodifluoromethoxy)phenyl)carbamoyl)-1-isopropyl-1H-benzo[d]imidazole-7-carboxylicacid (13c). To a mixture of methyl5-(4-(chlorodifluoromethoxy)phenyl)carbamoyl)-1-isopropyl-1H-benzo[d]imidazole-7-carboxylate (13b, 10 mg, 0.023 mmol, 1 eq) in THF (1 mL),H₂O (1 mL) and MeOH (0.5 mL) at 20° C. was added LiOH.H₂O (1.92 mg,0.046 mmol, 2 eq) in one portion. The mixture was heated to 45° C. andstirred for 2 hours. LC-MS showed that the reactant was consumedcompletely and one main peak with the desired mass was detected. Thereaction mixture was concentrated under reduced pressure to removesolvent. The residue was poured into H₂O (0.5 mL) and acidified with 1NHCl to pH=5. The mixture was filtered, and the filter cake was washedwith 0.5 mL of H₂O and dried in vacuo to give the crude product. Thecrude residue 13c was obtained as a white solid and used into the nextstep without further purification.

N⁵-(4-(chlorodifluoromethoxy)phenyl)-N⁷-cyclopropyl-1-isopropyl-1H-benzo[d]imidazole-5,7-dicarboxamide(13). To a mixture of5-(4-(chlorodifluoromethoxy)phenyl)carbamoyl)-1-isopropyl-1H-benzo[d]imidazole-7-carboxylicacid (13c, 40 mg, 0.094 mmol, 1 eq) and cyclopropanamine (6.47 mg, 0.113mmol, 7.85 uL, 1.2 eq) in DMF (2 mL) at 20° C. was added HATU (39.48 mg,0.104 mmol, 1.1 eq) and DIEA (24.40 mg, 0.189 mmol, 32.88 uL, 2 eq) inone portion. The mixture was stirred at 20° C. for 12 h. LC-MS showed40% of reactant remained. One new peak was observed on LC-MS and 60% ofthe desired compound was detected. The reaction mixture was concentratedunder reduced pressure to remove solvent. EtOAc (15 mL) was added to theresidue. The organic layers were washed with H₂O (10 mL) and brine (10mL), dried by Na₂SO₄ and concentrated under reduced pressure to give thecrude product. The residue was purified by prep-TLC (SiO₂,EtOAc:MeOH=10:1) to give the title compound 13 as a white solid. MS masscalculated for [M+1]⁺ (C₂₂H₂₁ClF₂N₄O₃) requires m/z 463.1, LCMS foundm/z 463.1; ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 8.88 (d, J=4.3 Hz,1H), 8.61 (s, 1H), 8.48 (d, J=1.6 Hz, 1H), 7.96 (d, J=9.0 Hz, 2H), 7.89(d, J=1.6 Hz, 1H), 7.37 (d, J=9.0 Hz, 2H), 4.96 (quin, J=6.7 Hz, 1H),3.02-2.87 (m, 1H), 1.50 (d, J=6.7 Hz, 6H), 0.85-0.70 (m, 2H), 0.65-0.56(m, 2H).

Example 14N-(4-(chlorodifluoromethoxy)phenyl)-1-(1-hydroxycyclopropyl)methyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

Methyl3-bromo-4-(((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)amino)-5-nitrobenzoate(14b). A mixture of methyl3-bromo-4-(((1-hydroxycyclopropyl)methyl)amino)-5-nitrobenzoate(synthesized in similar fashion to 1c; 14a, 0.48 g, 1.39 mmol, 1 eq),imidazole (142.02 mg, 2.09 mmol, 1.5 eq) and TBDPSCl (458.70 mg, 1.67mmol, 428.69 uL, 1.2 eq) in DCM (5 mL) at 25° C. was stirred at 25° C.for 16 hrs. Water (10 ml) was added and the mixture was extracted withDCM (20mL×3). The organic layers were dried over Na₂SO₄ and concentratedto give the crude product. The crude residue was purified by columnchromatography to give lc as a yellow oil. ¹H NMR (400 MHz, CDCl₃-d) δ8.43 (d, J=2.0 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.55-7.48 (m, 4H),7.39-7.28 (m, 6H), 6.94-6.84 (m, 1H), 3.85 (s, 3H), 2.92 (d, J=4.4 Hz,2H), 0.89 (s, 9H), 0.84-0.79 (m, 2H), 0.39-0.29 (m, 2H).

Methyl3-amino-5-bromo-4-(((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)amino)benzoate(14c). A solution of methyl3-bromo-4-(((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)amino)-5-nitrobenzoate(14b, 634 mg, 1.09 mmol, 1 eq) and Fe (606.79 mg, 10.86 mmol, 10 eq) inAcOH (7 mL) was stirred at 35° C. for 1 hr. EtOAc (20 ml) was added andthe mixture was filtered. The filtrate was washed with water (20mL×3),the organic layers were dried over Na₂SO₄ and the mixture wasconcentrated. Compound 14c was obtained as a yellow oil and required nofurther purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.67-7.63 (m,4H), 7.54 (d, J=1.7 Hz, 1H), 7.37-7.30 (m, 6H), 7.17 (d, J=1.8 Hz, 1H),3.79 (s, 3H), 2.84 (s, 2H), 1.00-0.98 (m, 9H), 0.76-0.67 (m, 2H),0.33-0.21 (m, 2H).

Methyl7-bromo-1-((1-(tert-butyldiphenylsilypoxy)cyclopropyl)methyl)-1H-benzo[d]imidazole-5-carboxylate(14d). A solution of methyl3-amino-5-bromo-4-(((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyDamino)benzoate(14c, 0.6 g, 1.08 mmol, 1 eq) and TsOH (18.66 mg, 0.108 mmol, 0.1 eq) inCH(OMe)₃ (10 mL) was stirred at 100° C. for 1 hr. The crude product waswashed with TMBE/PE, the mixture was filtrated and the solid wasconcentrated. No further purification was required. Compound 14d wasobtained as a yellow solid. ¹H NMR (400 MHz, CDCl₃-d) δ 8.46 (s, 1H),8.38 (s, 1H), 8.12 (s, 1H), 7.61 (d, J=7.1 Hz, 4H), 7.48-7.41 (m, 2H),7.39-7.33 (m, 4H), 4.52 (s, 2H), 3.98 (s, 3H), 1.05-0.93 (m, 11H),0.67-0.54 (m, 2H).

Methyl1-((1-((tert-butyldiphenylsilypoxy)cyclopropyl)methyl)-7-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylate(14f). To a solution of methyl7-bromo-1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-1H-benzo[d]imidazole-5-carboxylate(14d, 440 mg, 0.781 mmol, 1 eq) and 12e (116.09 mg, 0.934 mmol, 1.2 eq)in dioxane (5 mL) and H₂O (1 mL) under N₂ was added K₃PO₄ (497.19 mg,2.34 mmol, 3 eq) and Pd(dppf)Cl₂ (28.56 mg, 0.039 mmol, 0.05 eq). Themixture was stirred at 100° C. for 4 hrs. The mixture was concentrated,and the residue was purified by column chromatography. Compound 14f wasobtained as a yellow solid. ¹H NMR (400 MHz, CDCl₃-d) δ 9.20 (s, 1H),8.60-8.52 (m, 2H), 8.39 (s, 2H), 7.70 (d, J=1.5 Hz, 1H), 7.34-7.23 (m,6H), 7.16-7.09 (m, 4H), 3.92 (s, 3H), 3.36 (s, 2H), 0.87-0.76 (m, 11H),0.30-0.23 (m, 2H).

1-((1-((Tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-7-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylicacid (14g). To a solution of methyl1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-7-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylate(14f, 360 mg, 0.64 mmol, 1 eq) in THF (3 mL), MeOH and H₂O (2 mL) at 25°C. was added LiOH.H₂O (40.26 mg, 0.96 mmol, 1.5 eq). The reaction wasstirred at 25° C. for 3 hrs. The reaction mixture was concentrated underreduced pressure. Water (5 ml) was added and the mixture was extractedwith EtOAc (10 ml). Aqueous HCl (1M) was added until the aqueous phasereached pH=3˜4. The aqueous phase was again extracted with EtOAc (10mL×3), the organic layers were dried over Na₂SO₄, filtered andconcentrated, to give the crude product. No further purification wasrequired. Compound 14g was obtained as a red solid.

1-((1-((Tert-butyldiphenylsilypoxy)cyclopropyl)methyl)-N-(4-(chlorodifluoromethoxy)phenyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide(14i). To a solution of1-((1-((tert-butyldiphenylsily0oxy)cyclopropyl)methyl)-7-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylicacid (14 g, 90 mg, 0.164 mmol, 1 eq) and 1 h (38.10 mg, 0.197 mmol, 1.2eq) in DMF (3 mL) at 25° C. was added DIPEA (63.59 mg, 0.492 mmol, 85.71uL, 3 eq) and HATU (93.55 mg, 0.246 mmol, 1.5 eq). The mixture wasstirred at 25° C. for 12 hrs. EtOAc (10 ml) was added, the mixture waswashed with water (10 mL×5), the organic layers were dried over Na₂SO₄and concentrated to give the crude product. The residue was purified bycolumn chromatography. Compound 14i was obtained as a light-yellowsolid.

N-(4-(chlorodifluoromethoxy)phenyl)-1-((1-hydroxycyclopropyl)methyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide(14). To a solution of1-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methyl)-N-(4-(chlorodifluoromethoxy)phenyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide(14i, 0.03 g, 0.041 mmol,1 eq) in dry THF (3 mL) at 25° C. under N₂ wasadded TBAF (1M, 41.42 uL, 1 eq). The mixture was stirred at 25° C. for 2hrs and was concentrated. The residue was purified by prep-HPLC (NH₄HCO₃condition, column: Waters Xbridge Prep OBD C18 150*30 10 u; mobilephase: [water (10 mM NH₄HCO₃)-ACN]; B %: 35%-55%, 10 min) to yield thetitle compound 14 as a yellow solid. MS mass calculated for [M+1]⁺(C₂₃H₁₈ClF₂N₅O₃) requires m/z 486.1, LCMS found m/z 486.1; ¹H NMR (400MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.33 (s, 1H), 9.04 (s, 2H), 8.53 (s, 2H),7.98-7.93 (m, J=9.2 Hz, 2H), 7.81 (s, 1H), 7.42-7.33 (m, J=9.0 Hz, 2H),5.46 (s, 1H), 3.94 (s, 2H), 0.61-0.52 (m, 2H), 0.49-0.41 (m, 2H).

Example 15N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-2-(difluoromethyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

Methyl 3-bromo-4-(cyclopropylamino)-5-(2,2-difluoroacetamido)benzoate(15c). To a solution of methyl3-amino-5-bromo-4-(cyclopropylamino)benzoate (synthesized in similarfashion to id; 15a, 200 mg, 0.701 mmol, 1 eq) in DCM (8 mL) at 0° C. wasadded TEA (212.93 mg, 2.10 mmol, 3 eq) and 2,2-difluoroacetic anhydride(15b) (122.08 mg, 0.701 mmol, 1 eq). The mixture was stirred at 15° C.for 2 hr under N₂ atmosphere. LCMS showed a peak with desired MS wasdetected. The reaction mixture was concentrated. The crude product waspurified by prep-TLC (petroleum ether:ethyl acetate=3:1, R_(f)=0.4) togive 15c as a yellow solid.

Methyl7-bromo-1-cyclopropyl-2-(difluoromethyl)-1H-benzo[d]imidazole-5-carboxylate(1d). To a solution of 15d (80 mg, 0.220 mmol, 1 eq) in toluene (3 mL)was added AcOH (1.32 mg, 0.022 mmol, 10 eq). The mixture was stirred at60° C. for 16 hr. LCMS showed a peak with desired MS. The reactionmixture was concentrated, and the crude product was purified by prep-TLC(petroleum ether:ethyl acetate=1:1, R_(f)=0.4) to give 15d as a yellowsolid. ¹H NMR (400 MHz, CDCl₃-d) δ 8.43 (d, J=1.3 Hz, 1H), 8.29 (d,J=1.3 Hz, 1H), 7.18-6.85 (m, 1H), 3.97 (s, 3H), 3.70-3.60 (m, 1H),1.46-1.39 (m, 2H), 1.39-1.34 (m, 2H)

7-Bromo-1-cyclopropyl-2-(difluoromethyl)-1H-benzo[d]imidazole-5-carboxylicacid (15e). To a solution of 15d (1520 mg, 0.058 mmol, 1 eq) in THF (1mL), MeOH (1 mL) and H₂O (0.5 mL) was added LiOH.H₂O (4.86 mg, 0.116mmol, 2 eq). The mixture was stirred at 50° C. for 2 hr. LCMS showed apeak with desired MS. The mixture was concentrated and poured into H₂O(1 mL), and the pH was adjusted to 5 by HCl (1M in H₂O). The mixture wasconcentrated to give 15e as a yellow solid. ¹H NMR (400 MHz, CDCl₃-d) δ8.49 (s, 1H), 8.32 (d, J=1.3 Hz, 1H), 7.04-6.89 (m, 1H), 3.65 (br dd,J=3.4, 7.2 Hz, 1H), 1.46-1.41 (m, 2H), 1.37 (br s, 2H).

7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-2-(difluoromethyl)-1H-benzo[d]imidazole-5-carboxamide(15g). A mixture of 15e (18 mg, 0.054 mmol, 1 eq), 1h (15.79 mg, 0.082mmol, 1.5 eq), HATU (31.01 mg, 0.082 mmol, 1.5 eq) and DIEA (21.08 mg,0.163 mmol, 3 eq) in DMF (1 mL) was stirred at 15° C. for 2 hr. LCMSshowed a peak with desired MS. The reaction mixture was concentrated,and the crude product was purified by prep-TLC (petroleum ether:ethylacetate=2:1, R_(f)=0.5) to give 15g as a yellow solid. ¹H NMR (400 MHz,CDCl₃-d) δ 8.20 (d, J=1.5 Hz, 1H), 8.16 (d, J=1.5 Hz, 1H), 7.85 (s, 1H),7.72 (d, J=9.0 Hz, 2H), 7.30 (br s, 2H), 7.04 (s, 1H), 3.72 (br s, 1H),1.47-1.42 (m, 2H), 1.37 (br d, J=4.4 Hz, 2H).

N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-2-(difluoromethyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide(15). A mixture of 15g (35 mg, 0.069 mmol, 1 eq), pyrimidin-5-ylboronicacid (25.68 mg, 0.207 mmol, 3 eq), Pd(dppf)Cl₂ (5.05 mg, 6.91 umol, 0.01eq), K₃PO₄ (43.99 mg, 0.207 mmol, 3 eq) in dioxane (2 mL) and H₂O (0.2mL) was degassed and purged with N₂ 3 times. The reaction mixture wasstirred at 100° C. for 8 hr under N₂ atmosphere. LCMS showed a peak withdesired MS. The reaction mixture was concentrated, and the crude productwas purified by prep-TLC (petroleum ether:ethyl acetate=0:1, R_(f)=0.45)to give the title compound 15 as a white solid. MS mass calculated for[M+H]⁺ (C₂₃H₁₆ClF₄N₅O₂) requires m/z 506.1, LCMS found m/z 506.1. ¹H NMR(400 MHz, CH₃OD-d4) δ 9.29 (s, 1H), 9.15 (s, 2H), 8.50 (d, J=1.5 Hz,1H), 8.02 (d, J=1.5 Hz, 1H), 7.86 (d, J=9.0 Hz, 2H), 7.48-7.21 (m, 3H),3.45 (td, J=3.3, 7.1 Hz, 1H), 0.80 (br s, 2H), 0.60 (br d, J=6.6 Hz,2H).

Example 16N-(4-(chlorodifluoromethoxy)phenyl)-1-(1-hydroxy-2-methylpropan-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

Methyl 3-bromo-4-(1-hydroxy-2-methylpropan-2-yl)amino)-5-nitrobenzoate(16b). A mixture of methyl 3-bromo-4-fluoro-5-nitrobenzoate (1a, 300 mg,1.08 mmol), 2-amino-2-methyl-propan-1-ol (115.41 mg, 1.29 mmol), TEA(131.02 mg, 1.29 mmol) in EtOH (5 mL) was stirred at 15° C. for 3 hr.The reaction mixture was concentrated, and the crude product waspurified by prep-TLC (petroleum ether:ethyl acetate=3:1, R_(f)=0.5) togive 16b as a yellow oil. ¹H NMR (400 MHz, CDCl₃-d) δ 8.41 (d, J=2.0 Hz,1H), 8.39 (d, J=2.0 Hz, 1H), 5.06 (br s, 1H), 3.95 (s, 3H), 3.48 (s,2H), 1.19 (s, 6H).

Methyl4-((1-hydroxy-2-methylpropan-2-yl)amino)-3-nitro-5-(pyrimidin-5-yl)benzoate(16d). A mixture of 16b (200 mg, 0.576 mmol), 16c (142.76 mg, 1.15mmol), Pd(dppf)Cl₂ (21.08 mg, 0.029 mmol), K₃PO₄ (366.86 mg, 1.73 mmol)in dioxane (4 mL) and H₂O (0.4 mL) was degassed and purged with N₂ 3times. The mixture was stirred at 110° C. for 6 hr under a N₂atmosphere. LCMS showed a peak with desired MS. The reaction mixture wasconcentrated, and the crude product was purified by prep-TLC (petroleumether:ethyl acetate=0:1, R_(f)=0.4) to give 16d as a yellow solid. ¹HNMR (400 MHz, CDCl₃-d) δ 9.25 (s, 1H), 9.02 (s, 2H), 8.63 (d, J=2.0 Hz,1H), 8.14 (d, J=2.0 Hz, 1H), 5.79 (s, 1H), 4.02-3.93 (m, 3H), 3.15 (brs, 2H), 0.76 (s, 6H).

Methyl3-amino-4-((1-hydroxy-2-methylpropan-2-yl)amino)-5-(pyrimidin-5-yl)benzoate(16e). To a solution of 16d (70 mg, 0.202 mmol) in EtOH (4 mL) was addedFe (112.87 mg, 2.02 mmol) and NH₄Cl (108.11 mg, 2.02 mmol). The mixturewas stirred at 80 ° C. for 0.5 hr. LCMS showed a peak with desired MS.The mixture was filtered through a Celite® pad and the filtrate wasconcentrated. The crude product was purified by prep-TLC (petroleumether:ethyl acetate=10:1, R_(f)=0.3) to give 16e as a yellow solid. ¹HNMR (400 MHz, CDCl₃-d) δ 9.19 (s, 1H), 8.90 (s, 2H), 7.48 (d, J=2.0 Hz,1H), 7.39 (d, J=2.0 Hz, 1H), 3.91 (s, 3H), 3.50 (s, 2H), 3.25 (s, 2H),0.76 (s, 6H).

Methyl1-(1-(dimethoxymethoxy)-2-methylpropan-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylate(16f). To a solution of 16e (20 mg, 0.063 mmol) in trimethoxymethane(1.94 g, 18.24 mmol) was added PTSA (1.09 mg, 6.32 umol). The mixturewas stirred at 80° C. for 1 hr. LCMS showed a peak with desired MS. Thereaction mixture was concentrated and the crude residue was purified byprep-TLC (ethyl acetate:methanol=10:1, R_(f)=0.4) to give 16f as ayellow oil. ¹H NMR (400 MHz, CDCl₃-d) δ 9.33 (s, 1H), 8.84 (s, 2H), 8.60(s, 1H), 8.31 (s, 1H), 7.70 (s, 1H), 4.85 (s, 1H), 3.96 (s, 3H), 3.58(s, 2H), 3.09 (s, 6H), 1.44 (s, 5H), 1.42 (br s, 1H).

Methyl1-(1-hydroxy-2-methylpropan-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylate(16g). To a solution of 16f (10 mg, 0.025 mmol) in MeOH (2 mL) was addedHCl (0.1M, 499.47 uL). The mixture was stirred at 15° C. for 3 hr. LCMSshowed a peak with desired MS. The reaction mixture was concentrated togive 16g as a yellow oil. The product was used to the next step withoutpurification.

1-(1-Hydroxy-2-methylpropan-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylicacid (16h). To a solution of 16g (10 mg, 0.031 mmol) in MeOH (1 mL), THF(1 mL) and H₂O (0.5 mL) was added LiOH.H₂O (3.86 mg, 0.092 mmol). Themixture was stirred at 50° C. for 3 hr. LCMS showed a peak with desiredMS. The mixture was concentrated, and the residue was poured into H₂O (1mL). The pH of the solution was adjusted to 4 by addition of HCl (1M inH₂O ) to give 16h as a white solid. The product was used in the nextstep without further purification.

N-(4-(chlorodifluoromethoxy)phenyl)-1-(1-hydroxy-2-methylpropan-2-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide(16). A mixture of 16h (10 mg, 0.032 mmol),4-(chlorodifluoromethoxy)aniline (1h), HATU (18.26 mg, 0.048 mmol) andDIEA (12.41 mg, 0.096 mmol) in DMF (1 mL) was stirred at 15° C. for 3hr. LCMS showed a peak with desired MS. The reaction mixture wasconcentrated, and the residue was purified by prep-HPLC (NH₄HCO₃,column: Agela Durashell C18 150*25 5 u; mobile phase: [water (10 mMNH₄HCO₃)-ACN]; B %: 35%-65%,10 min) to give the title compound 16 as awhite solid. MS mass calculated for [M+1]⁺ (C₂₃H₂₀ClF₂N₅O₃) requires m/z488.1, LCMS found m/z 488.1. ¹H NMR (400 MHz, MeOD-d₄) δ 9.31 (s, 1H),8.98 (s, 2H), 8.55 (s, 1H), 8.47 (d, J=1.8 Hz, 1H), 7.83 (d, J=9.0 Hz,2H), 7.71 (d, J=1.8 Hz, 1H), 7.29 (d, J=9.0 Hz, 2H), 3.56 (s, 2H), 1.41(s, 6H).

Example 17N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-fluoro-1H-pyrazol-5-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide

4-Fluoro-1-(4-methoxybenzyl)-1H-pyrazole (17b). To a solution of4-fluoro-1H-pyrazole (17a, 1 g, 11.62 mmol) in THF (15 mL) at 0° C. wasadded NaH (697.06 mg, 17.43 mmol, 60% purity). After 10 min stirring,1-(chloromethyl)-4-methoxy-benzene (2.18 g, 13.94 mmol) was added slowlyto the reaction mixture. The resulting solution was stirred for 16 hr atto 15° C. TLC (petroleum ether:ethyl acetate=5:1, R_(f)=0.4) indicated anew spot was generated. LCMS showed a peak with desired MS. The reactionmixture was concentrated. To the residue was added H₂O (20 mL) and theaqueous phase was extracted with ethyl acetate (60 mL). The organiclayers were washed with brine (5 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bysilica gel column chromatography (petroleum ether:ethylacetate=50:1-30:1) to give 17b as a yellow oil. ¹H NMR (400 MHz,CDCl₃-d) δ 7.35 (d, J=4.0 Hz, 1H), 7.21-7.17 (m, 3H), 6.91-6.87 (m, 2H),5.14 (s, 2H), 3.81 (s, 3H).

5-Bromo-4-fluoro-1-(4-methoxybenzyl)-1H-pyrazole (17d). To a solution of17b (850 mg, 4.12 mmol) in THF (15 mL) at −70° C. was added a solutionof n-BuLi (2.5 M, 2.47 mL, 1.5 eq) slowly. The mixture was stirred for15 min while maintaining the temperature below −60° C. A solution of1,2-dibromo-1,1,2,2-tetrachloroethane (17c, 1.61 g, 4.95 mmol) in THF (1mL) was added to the reaction mixture and the resulting solution wascontinuously stirred for an additional 2 hr. TLC (petroleum ether:ethylacetate=3:1, R_(f)=0.6) indicated a new spot was generated. LCMS showeda peak with desired MS. The reaction mixture was quenched with theaddition of water H₂O (20 mL) and followed by the addition of ethylacetate (80 mL). After quenching the reaction, the reaction mixture waspoured into a separatory funnel and separated. The organic layers wereconcentrated and the crude product was purified by silica gel columnchromatography (petroleum ether:ethyl acetate=45:1˜10:1) to give 17d asa yellow solid. ¹H NMR (400 MHz, CDCl₃-d) δ 7.43 (d, J=4.8 Hz, 1H), 7.20(d, J=8.8 Hz, 2H), 6.89-6.85 (m, 2H), 5.23 (s, 2H), 3.80 (s, 3H).

4-Fluoro-1-(4-methoxybenzyl)-5-(trimethylstannyl)-1H-pyrazole (17e). Amixture of 17d (300 mg, 1.05 mmol), trimethyl(trimethylstannyl)stannane(413.68 mg, 1.26 mmol), Pd(PPh₃)₄ (121.59 mg, 0.105 mmol) in toluene (5mL) was degassed and purged with N₂ 3 times. The mixture was stirred at130° C. for 16 hr under N₂ atmosphere. TLC (petroleum ether:ethylacetate=3:1, R_(f)=0.7) indicated a new spot was generated. LCMS showeda peak with desired MS was detected. The reaction mixture was quenchedby addition of KF (5 mL), followed by the addition of ethyl acetate (40mL). After quenching the reaction, the reaction mixture was poured intoseparatory funnel and separated. The organic layers were concentratedand the residue was purified by prep-TLC (petroleum ether:ethylacetate=3:1, R_(f)=0.7) to give 17e as a yellow oil. ¹H NMR (400 MHz,CDCl₃-d) δ 7.40 (d, J=4.8 Hz, 1H), 6.92 (t, J=8.4 Hz, 2H), 6.88-6.83 (m,2H), 5.21 (s, 2H), 3.79 (s, 3H), 0.25 (s, 9H).

N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-fluoro-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(17g). A mixture of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(10a, 74.58 mg, 0.163 mmol), 17e (120.00 mg, 0.325 mmol) and Pd(PPh₃)₄(37.58 mg, 0.033 mmol) in DMSO (3 mL) was degassed and purged with N₂ 3times. The mixture was stirred at 100° C. for 16 hr under N₂ atmosphere.LCMS showed a peak with desired MS was detected. The mixture wasquenched with the addition of water (40 mL) and the mixture wasextracted with ethyl acetate (60 mL×3). The combined organic layers weredried over Na₂SO₄, filtered and concentrated to give the crude product.The crude residue was purified by prep-TLC (ethyl acetate:methanol=10:1,R_(f)=0.6) to give 17g as a yellow oil. ¹H NMR (400 MHz, CDCl₃-d) δ 8.49(d, J=1.5 Hz, 1H), 8.13-8.08 (m, 1H), 7.87 (s, 1H), 7.72 (s, 2H),7.61-7.56 (m, 2H), 7.49 (s, 2H), 7.28 (br s, 1H), 6.77 (d, J=8.6 Hz,2H), 6.70-6.65 (m, 2H), 5.70-5.57 (m, 1H), 5.10-4.92 (m, 3H), 3.91-3.78(m, 2H), 3.66 (s, 3H), 1.67 (d, J=6.6 Hz, 2H), 1.34 (d, J=6.6 Hz, 3H),1.15 (d, J=6.6 Hz, 3H).

N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-fluoro-1H-pyrazol-5-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(17). A solution of 17g (80 mg, 0.137 mmol) in TFA (2 mL) was stirred at15° C. for 16 hr. LCMS showed a peak with desired MS was detected. Thereaction mixture was concentrated. The crude residue was purified byprep-TLC (ethyl acetate:methanol=10:1, R_(f)=0.4) to give the titlecompound 17 as a white solid. MS mass calculated for [M+H]⁺(C₂₁H₁₇ClF₃N₅O₂) requires m/z 464.1, LCMS found m/z 464.0. ¹H NMR (400MHz, MeOD-d₄) δ 8.56 (br s, 1H), 8.43 (br s, 1H), 7.93 (d, J=1.8 Hz,1H), 7.87-7.80 (m, 3H), 7.29 (d, J=9.0 Hz, 2H), 4.67 (br s, 1H), 1.43(d, J=6.6 Hz, 6H).

Example 18N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-7-(4-fluoro-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide

N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-7-(4-fluoro-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide(18b). To a mixture of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-1H-benzo[d]imidazole-5-carboxamide(synthesized in similar fashion to 10a; 18a, 100 mg, 0.219 mmol, 1 eq)and 4-fluoro-1-(4-methoxybenzyl)-5-(trimethylstannyl)-1H-pyrazole (17e,80.81 mg, 0.219 mmol, 1 eq) in DMSO (1.5 mL) was added Pd(PPh₃)₄ (12.65mg, 0.011 mmol, 0.05 eq). The reaction mixture was stirred at 100° C.for 16 hr. LCMS showed a peak with desired MS was detected. The mixturewas poured into water (10 mL) and the mixture was extracted with EtOAc(10 mL×2). The combined organic layers were concentrated and purified byprep-TLC (EtOAc:MeOH=10:1, R_(f)=0.6) to give 18b as a yellow oil.

N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-7-(4-fluoro-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide(18).N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-7-(4-fluoro-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide(18b, 120 mg, 0.206 mmol, 1 eq) was dissolved in TFA (3 mL). Thereaction mixture was stirred at 20° C. for 2 hr. LCMS showed a peak withdesired MS was detected. The solvent was evaporated under vacuum and theresidue was dissolved in EtOAc (5 mL). The organic layer was washed withsaturated NaHCO₃ (2 mL), brine (2 mL) and concentrated to give the cruderesidue that was purified by prep-TLC (EtOAc:MeOH=10: 1, R_(f)=0.3) togive the title compound 18 as a white solid. MS mass calculated for[M+H]⁺ (C₂₁H₁₅ClF₃N₅O₂) requires m/z 462.1, LCMS found m/z 462.0. ¹H NMR(400 MHz, CDCl₃-d) δ 9.55 (br s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.92(s, 1H), 7.82-7.75 (m, 2H), 7.50 (d, J=4.6 Hz, 1H), 7.22 (br d, J=8.8Hz, 2H), 3.42 (br d, J=3.3 Hz, 1H), 0.80-0.63 (m, 4H).

Example 19N-(4-(chlorodifluoromethoxy)phenyl)-1-(1,1-dioxidothietan-3-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

N-(4-(chlorodifluoromethoxy)phenyl)-7-(pyrimidin-5-yl)-1-(thietan-3-yl)-1H-benzo[d]imidazole-5-carboxamide(19c). To a mixture of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(thietan-3-yl)-1H-benzo[d]imidazole-5-carboxamide(19a, 130 mg, 0.266 mmol, 1 eq), pyrimidin-5-ylboronic acid (synthesizedin a similar fashion to 2c; 19b, 98.87 mg, 0.798 mmol, 3 eq), K₃PO₄(169.38 mg, 0.798 mmol, 3 eq) in dioxane (2mL) and H₂O (0.2mL) under N₂was added Pd(dppf)Cl₂ (19.46 mg, 0.27 mmol, 0.1 eq). The mixture wasstirred at 100° C. for 16 hours. LCMS showed desired MS. The mixture waspoured into water, and then was extracted with EtOAc. The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the crude product. The residue waspurified by prep-TLC (ethyl acetate:methanol=10:1, R_(f)=0.30) to afford19c as a white solid. ¹H NMR (400 MHz, CDCl₃-d) δ 9.36 (s, 1H), 8.82 (s,2H), 8.43 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.71 (s, 1H), 7.66 (br d,J=8.8 Hz, 2H), 7.22 (br s, 2H), 5.06 (quin, J=8.2 Hz, 1H), 3.63 (t,J=9.0 Hz, 2H), 3.14 (t, J=9.0 Hz, 2H).

N-(4-(chlorodifluoromethoxy)phenyl)-1-(1,1-dioxidothietan-3-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide(19). To a mixture ofN-(4-(chlorodifluoromethoxy)phenyl)-7-(pyrimidin-5-yl)-1-(thietan-3-yl)-1H-benzo[d]imidazole-5-carboxamide(19c, 40 mg, 0.082 mmol, 1 eq) was dissolved in DCM (2 mL) at 0° C. wasadded saturated aqueous sodium hydrogen carbonate and mCPBA (70.74 mg,0.328 mmol, 80% purity, 4 eq). The reaction mixture was stirred at 15°C. for 16 hours. LCMS showed desired MS. The mixture was poured intowater, and then was extracted with EtOAC. The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo togive the required product. The residue was purified by prep-TLC (ethylacetate:methanol=10:1, R_(f)=0.37) to afford the title compound 19 as awhite solid. MS mass calculated for [M+1]⁺ (C₂₂H₁₆ClF₂N₅O₄S) requiresm/z 520.1, LCMS found m/z 520.0. NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H),9.38 (s, 1H), 9.03 (s, 2H), 8.83 (s, 1H), 8.55 (s, 1H), 7.95 (br d,J=8.8 Hz, 2H), 7.88-7.77 (m, 1H), 7.38 (br d, J=8.6 Hz, 2H), 4.94-4.83(m, 1H), 4.74 (br d, J=13.2 Hz, 2H), 4.41-4.26 (m, 2H).

Example 20N-(4-(chlorodifluoromethoxy)phenyl)-6-fluoro-1-isopropyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

Methyl 2-fluoro-4-(isopropylamino)-5-nitrobenzoate (20b). To a solutionof methyl 2,4-difluoro-5-nitrobenzoate (20a, 2 g, 9.21 mmol, 1 eq) inTHF (10 mL) at 15° C. was added TEA (2.80 g, 27.63 mmol, 3.85 mL, 3 eq)drop-wise, followed by propan-2-amine (653.37 mg, 11.05 mmol, 949.67 uL,1.2 eq) drop-wise. The resulting mixture was stirred at 0° C. for 1 hr.TLC (petroleum ether:EtOAc=5:1, R_(f)=0.50) indicated 20a was consumedcompletely, and one major new spot was detected. The aqueous phase wasextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The product was used in the next step withoutfurther purification. Compound 20b was obtained as a yellow solid. ¹HNMR (400 MHz, CDCl₃-d) δ 8.91 (d, J=7.8 Hz, 1H), 8.29 (br d, J=4.9 Hz,1H), 6.52 (d, J=13.7 Hz, 1H), 3.90 (s, 3H), 3.83-3.70 (m, 1H), 1.36 (d,J=6.4 Hz, 6H).

Methyl 3-bromo-2-fluoro-4-(isopropylamino)-5-nitrobenzoate (20c). To asolution of methyl 2-fluoro-4-(isopropylamino)-5-nitrobenzoate (20b, 2g, 7.81 mmol, 1 eq) in DCM (5 mL) was added Br₂ (2.00 g, 12.51 mmol,645.16 uL, 1.60 eq). The mixture was stirred at 0° C. for 1 hr. TLC(petroleum ether:EtOAc=5:1, R_(f)=0.50) indicated 20b was consumedcompletely. The reaction mixture was quenched by the addition ofsaturated Na₂SO₃ (5 mL). The residue was diluted with H₂O (20 mL) andextracted with DCM (10 mL×3). The combined organic layers were washedwith brine (30 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the crude product. The residue was purified bysilica gel column chromatography (SiO₂, petroleum ether:ethylacetate=10:1) to afford 20c as a yellow solid. ¹H NMR (400 MHz, CDCl₃-d)δ 8.72 (d, J=7.3 Hz, 1H), 4.49-4.34 (m, 1H), 3.93 (s, 3H), 1.29-1.27 (m,6H).

Methyl 5-amino-3-bromo-2-fluoro-4-(isopropylamino)benzoate (20d). To asolution of methyl 3-bromo-2-fluoro-4-(isopropylamino)-5-nitrobenzoate(20c, 1 g, 2.98 mmol, 1 eq) in EtOH (20 mL) was added Fe (1.67 g, 29.84mmol, 10 eq) and NH₄Cl (1.60 g, 29.84 mmol, 1.04 mL, 10 eq). The mixturewas stirred at 80° C. for 6 hr. TLC (petroleum ether:EtOAc=3:1)indicated 20c was consumed completely. The reaction mixture wasconcentrated under reduced pressure. The residue was diluted with H₂O(20 mL) and extracted with EtOAc (10 mL×3). The combined organic layerswere washed with brine (30 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product. Theresidue was purified by column chromatography (SiO₂, petroleumether/ethyl acetate=10/1 to 1:1). Compound 20d was obtained as a brownoil. ¹H NMR (400 MHz, CDCl3-d) δ 7.21 (d, J=6.8 Hz, 1H), 3.90 (s, 3H),3.80-3.71 (m, 1H), 1.17 (d, J=6.4 Hz, 6H).

Methyl 7-bromo-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxylate(20e). To a solution of methyl5-amino-3-bromo-2-fluoro-4-(isopropylamino)benzoate (20d, 180 mg, 0.590mmol, 1 eq) in CH(OMe)₃ (2 mL) was added p-TsOH (10.16 mg, 0.059 mmol,0.1 eq). The mixture was stirred at 100° C. for 1.5 hr. TLC (petroleumether:ethyl acetate=1:1) indicated 20d was consumed completely. Thereaction mixture was concentrated under reduced pressure. The residuewas diluted with H₂O (20 mL) and extracted with EA (10 mL×3). Thecombined organic layers were washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thecrude product. The residue was purified by prep-TLC (SiO₂, petroleumether/ethyl acetate=1:1). Compound 20e was obtained as a white solid. ¹HNMR (400 MHz, CDCl₃-d) δ 8.34 (d, J=5.9 Hz, 1H), 8.15 (s, 1H), 5.64(quind, J=6.7, 13.4 Hz, 1H), 3.97 (s, 3H), 1.65 (d, J=6.4 Hz, 6H).

7-Bromo-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxylic acid(20f). To a solution of methyl7-bromo-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxylate (20e,140 mg, 0.444 mmol, 1 eq) in THF (5 mL), MeOH (5 mL) and H₂O (2 mL) wasadded LiOH.H₂O (46.60 mg, 1.11 mmol, 2.5 eq). The mixture was stirred at50° C. for 12 hr. TLC (petroleum ether:ethyl acetate=1:1) indicated 20ewas consumed completely. The mixture was adjusted to pH=5 with aqueousHCl (1M) and concentrated to give 20f as a white solid, which was usedin the next step without further purification.

7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(20g). To a solution of7-bromo-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxylic acid(20f, 70 mg, 0.232 mmol, 1 eq) in DMF (2 mL) was added HATU (106.07 mg,0.279 mmol, 1.2 eq), 4-[chloro(difluoro)methoxy]aniline (1h, 49.50 mg,0.256 mmol, 1.1 eq) and DIEA (90.13 mg, 0.697 mmol, 121.47 uL, 3 eq).The mixture was stirred at 50° C. for 3 hr. TLC (petroleum ether:ethylacetate=1:1) indicated 20f consumed completely. The reaction mixture wasconcentrated under reduced pressure. The residue was diluted with H₂O(10 mL) and extracted with EtOAc (10 mL×3). The combined organic layerswere washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product. Theresidue was purified by column chromatography (SiO₂, petroleumether/ethyl acetate=10/1 to 1:1). Compound 20g was obtained as a whitesolid. ¹H NMR (400 MHz, MeOD-d₄) δ 8.57 (s, 1H), 8.01 (d, J=6.4 Hz, 1H),7.82 (d, J=8.8 Hz, 2H), 7.30 (d, J=9.3 Hz, 2H), 5.70 (td, J=6.7, 13.6Hz, 1H), 1.67 (d, J=6.8 Hz, 6H).

N-(4-(chlorodifluoromethoxy)phenyl)-6-fluoro-1-isopropyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide(20). To a solution of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-fluoro-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(20g, 50 mg, 0.105 mmol, 1 eq) in dioxane (2.5 mL) and H₂O (0.5 mL) wasadded Pd(dppf)Cl₂ (7.68 mg, 0.01 mmol, 0.1 eq), pyrimidin-5-ylboronicacid (38.99 mg, 0.315 mmol, 3 eq) and K₃PO₄ (66.80 mg, 0.315 mmol, 3eq). The mixture was stirred at 100° C. for 6 hr. LC-MS showed 20g wasconsumed completely and one main peak with desired MS was detected. Themixture was concentrated to give the crude product. The residue waspurified by prep-HPLC (NH₄HCO₃ condition, column: Waters Xbridge 150*5010 u; mobile phase: [water (10 mM NH₄HCO₃)-MeOH]; B %: 55%-75%, 12 min)to afford the title compound 20 as a white solid. MS mass calculated for[M+H]⁺ (C₂₂H₁₇ClF₃N₅O₂) requires m/z 476.1, LCMS found m/z 476.1; ¹H NMR(400 MHz, CDCl₃-d) δ 9.42 (s, 1H), 8.93 (s, 2H), 8.74 (d, J=7.3 Hz, 1H),8.44 (br d, J=15.7 Hz, 1H), 8.18 (s, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.25(d, J=8.8 Hz, 2H), 3.96 (td, J=6.8, 13.3 Hz, 1H), 1.38 (d, J=6.8 Hz,6H).

Example 21N-(4-(chlorodifluoromethoxy)phenyl)-1-(2-(cyclopropylamino)-2-oxoethyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(2-(cyclopropylamino)-2-oxoethyl)-1H-benzo[d]imidazole-5-carboxamide(21c). To a mixture of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1H-benzo[d]imidazole-5-carboxamide(synthesized in a similar fashion to 2c; 21a, 80 mg, 0.192 mmol, 1 eq)and 2-chloro-N-cyclopropylacetamide (21b, 30.78 mg, 0.230 mmol, 1.2 eq)in DMF (1 mL) under N₂ was added K₂CO₃ (18.58 mg, 0.134 mmol, 0.7 eq).The mixture was stirred at 80° C. for 4 hours. TLC (ethylacetate:methanol=10:1, R_(f)=0.32) showed the reaction was completed.The mixture was poured into water (20 mL), and then was extracted withEtOAc (20 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the crude product.The residue was purified by prep-TLC (ethyl acetate:methanol=10:1,R_(f)=0.32) to give 21c as a white solid. ¹H NMR (400 MHz, MeOD-d₄) δ8.21 (d, J=6.2 Hz, 2H), 8.01 (s, 1H), 7.74 (d, J=8.9 Hz, 2H), 7.20 (brd, J=8.9 Hz, 2H), 5.19 (s, 2H), 2.61 (dt, J=3.7, 7.5 Hz, 1H), 0.65 (brd, J=5.1 Hz, 2H), 0.46 (br d, J=2.4 Hz, 2H).

N-(4-(chlorodifluoromethoxy)phenyl)-1-(2-(cyclopropylamino)-2-oxoethyl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide(21). To a solution of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(2-(cyclopropylamino)-2-oxoethyl)-1H-benzo[d]imidazole-5-carboxamide(21c, 10 mg, 0.019 mmol, 1 eq) and pyrimidin-5-ylboronic acid (21d, 4.82mg, 0.039 mmol, 2 eq) in dioxane (2 mL) and H₂O (0.4 mL) was addedPd(dppf)Cl₂ (1.42 mg, 1.95 umol, 0.1 eq) and K₃PO₄ (12.40 mg, 0.058mmol, 3 eq). The reaction mixture was stirred at 100° C. for 6 hr. LCMSshowed a peak with desired MS was detected. The reaction mixture wasconcentrated, the residue was dissolved in EtOAc (5 mL) and washed withH₂O (2 mL) and brine (5 mL). The organic layer was concentrated andpurified by prep-TLC (EtOAc:MeOH=5:1) to afford the title compound 21 asa white solid. MS mass calculated for [M+H]⁺ (C₂₄H₁₉ClF₂N₆O₃) requiresm/z 513.1, LCMS found m/z 513.1. ¹H NMR (400 MHz, MeOD-d₄) δ 8.91 (s,1H), 8.54 (s, 2H), 8.08 (d, J=1.5 Hz, 1H), 7.91 (s, 1H), 7.50-7.41 (m,3H), 6.92 (d, J=9.0 Hz, 2H), 4.32 (s, 2H), 2.05 (tt, J=3.9, 7.2 Hz, 1H),0.31-0.21 (m, 2H), 0.01-0.00 (m, 2H).

Example 22 General Procedure IN-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(thiazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide

The title compound was prepared using an analogous coupling reaction asoutlined in Scheme 9. This General Procedure I exemplifies Scheme 9 andprovides particular synthetic details as applied to the title compound.

N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(thiazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide(22).7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(10a, 100 mg, 0.218 mmol, 1 eq), tributyl(thiazol-4-yl)stannane (22b,97.89 mg, 0.262 mmol, 1.2 eq) and Pd(PPh₃)₄ (25.19 mg, 0.022 mmol, 0.1eq) were added to a microwave tube in dioxane (4 mL). The sealed tubewas heated to 150° C. for 3 hrs under microwave irradiation. Water (5ml) was added to the reaction mixture, and the extracted with EtOAc (10mL×2). The combined organic layers were concentrated, and the cruderesidue was purified by prep-HPLC (TFA condition, column: Luna C18100*30 5 u; mobile phase: [water (0.1%TFA)-ACN]; B %: 15%-50%, 10 min)to afford the title compound 22 as a yellow solid. MS mass calculatedfor [M+1]⁺ (C₂₁H₁₇ClF₂N₄O₂S) requires m/z 463.1, LCMS found m/z 463.0.¹H NMR (400 MHz, CDCl₃-d) δ 8.95-8.91 (m, 1H), 8.86 (d, J=1.6 Hz, 1H),8.40 (s, 1H), 8.03 (s, 1H), 7.84 (s, 1H), 7.74 (br d, J=8.8 Hz, 2H),7.50 (d, J=1.6 Hz, 1H), 7.24-7.15 (m, 2H), 4.53 (td, J=6.6, 13.3 Hz,1H), 1.26 (d, J=6.6 Hz, 6H).

Example 23N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(4H-1,2,4-triazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide

N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-((4-methoxybenzypamino)-1H-benzo[d]imidazole-5-carboxamide(23b). To a mixture of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(10a, 900 mg, 1.96 mmol) in DME (15 mL) was added PMBNH₂ (323.00 mg,2.35 mmol, 304.71 uL), NaOBu-t (565.70 mg, 5.89 mmol), XPhos (93.54 mg,0.196 mmol) and Pd₂(dba)₃ (179.68 mg, 0.196 mmol). The mixture wasstirred at 100° C. for 12 hr under N₂ atmosphere. LCMS showed a peakwith desired MS was detected. The reaction mixture was concentratedunder reduced pressure. The residue was diluted with water (5 mL) andextracted with EtOAc (5 mL×3). The combined organic layers were washedwith brine (5 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=3/1, 1/3) to afford 23b asa yellow solid. MS mass calculated for [M+1]⁺ (C₂₆H₂₅ClF₂N₄O₃) requiresm/z 515.2, LCMS found m/z 515.2. ¹H NMR (400 MHz, DMSO-d₆) δ 10.24 (s,1H), 8.38-8.36 (m, 1H), 7.93-7.89 (m, 2H), 7.78 (d, J=1.2 Hz, 1H), 7.38(d, J=8.6 Hz, 2H), 7.33 (br d, J=9.0 Hz, 2H), 7.04 (s, 1H), 6.91 (d,J=8.7 Hz, 2H), 6.01-5.94 (m, 1H), 5.32-5.23 (m, 1H), 4.40 (br d, J=5.3Hz, 2H), 3.72 (s, 3H), 1.57 (d, J=6.5 Hz, 6H).

7-Amino-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(23c). A solution ofN-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-((4-methoxybenzypamino)-1H-benzo[d]imidazole-5-carboxamide(23b, 100 mg, 0.194 mmol) in HCl/dioxane (40 mL) was stirred at 20° C.for 12 hr. LCMS showed desired MS was detected. The reaction mixture wasconcentrated under reduced pressure. The mixture was purified byprep-HPLC (NH₄HCO₃ condition, column: Agela Durashell C18 150*25 5 u;mobile phase: [water (10 mM NH4HCO3)-ACN]; B %: 35%-65%,10 min) to give23c as yellow solid. MS mass calculated for [M+1]⁺ (C₁₈H₁₇ClF₂N₄O₂)requires m/z 395.1, LCMS found m/z 395.1. ¹H NMR (400 MHz, MeOD-d₄) δ8.34 (br s, 1H), 7.82 (d, J=9.0 Hz, 2H), 7.69 (d, J=1.6 Hz, 1H), 7.29(d, J=9.2 Hz, 2H), 7.23 (d, J=1.6 Hz, 1H), 5.25-5.12 (m, 1H), 1.66 (d,J=6.7 Hz, 6H).

N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(4H-1,2,4-triazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide(23). To a solution of7-amino-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(23c, 14 mg, 0.035 mmol) and N-formamidoformamide (9.37 mg, 0.106 mmol)in pyridine (1.5 mL) was added chloro-trimethyl-silane (57.79 mg, 0.532mmol, 67.51 uL) and TEA (25.12 mg, 0.248 mmol, 34.55 uL). The mixturewas stirred at 100° C. for 18 hr. LCMS showed 23c was consumedcompletely and one main peak with desired mass was detected. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by prep-HPLC (column: Waters Atlantis T3 150*30*5 um;mobile phase: [water (0.225%FA)-ACN]; B %: 20%-60%, 13 min) to affordthe title compound 23 as a white solid. MS mass calculated for [M+1]⁺(C₂₀H₁₇ClF₂N₆O₂) requires m/z 447.1, LCMS found m/z 447.1. ¹H NMR (400MHz, CDCl₃-d) δ 8.50-8.45 (m, 3H), 8.23 (s, 2H), 7.91 (d, J=1.0 Hz, 1H),7.75 (d, J=8.8 Hz, 2H), 7.29 (br d, J=9.3 Hz, 2H), 3.74-3.61 (m, 1H),1.45 (d, J=6.4 Hz, 6H).

Example 24 General Procedure J(S)-N-(4-(chlorodifluoromethoxy)phenyl)-1-(5-oxopyrrolidin-3-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide

This General Procedure J provides particular synthetic details asapplied to the title compound. Additional compounds can be preparedaccording to this method by varying the coupling reagents.

3-Bromo-4-fluoro-5-nitrobenzoic acid (24b). To a solution of4-fluoro-3-nitrobenzoic acid (24a, 5 g, 27.01 mmol) in H₂SO₄ (30 mL) wasadded NBS (5.77 g, 32.41 mmol). The mixture was stirred at 60° C. for 6hr. The mixture was added to ice-water (2 L) drop-wise with vigorousstirring. The precipitate was filtered to afford 24b as a white solid.¹H NMR (400 MHz, CDCl₃-d) δ 8.72 (dd, J=2.2, 6.4 Hz, 1H), 8.58 (dd,J=2.2, 5.5 Hz, 1H).

3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluoro-5-nitrobenzamide(24c). A suspension of 3-bromo-4-fluoro-5-nitrobenzoic acid (24b, 150mg, 0.568 mmol) in SOCl₂ (2 mL) was stirred at 60° C. for 3 hours. Themixture was concentrated to obtain 3-bromo-4-fluoro-5-nitro-benzoylchloride (214 mg, crude) as a white solid. To a mixture of4-(chlorodifluoromethoxy)aniline (1h, 146.64 mg, 0.758 mmol) andpyridine (89.89 mg, 1.13 mmol, 91.72 uL) in THF (2 mL) under N₂ wasadded 3-bromo-4-fluoro-5-nitro-benzoyl chloride (213.97 mg, 0.758 mmol).The mixture was stirred at 20° C. for 3 hours. LCMS showed the desiredMS. The mixture was extracted with ethyl acetate (2 mL×3), the combinedorganic layers were washed with brine (5 mL×2), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byprep-TLC (SiO₂, petroleum ether:ethyl acetate=1: 1, R_(f)=0.3). Compound24c was obtained as a white solid.

(S)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-nitro-4-((5-oxopyrrolidin-3-yl)amino)benzamide(24e). To a mixture of3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluoro-5-nitrobenzamide(24c, 100 mg, 0.228 mmol) and (4S)-4-aminopyrrolidin-2-one (24d, 22.78mg, 0.228 mmol) in EtOH (2 mL) was added TEA (69.06 mg, 0.682 mmol,94.99 uL). The mixture was stirred at 50° C. for 3 h. LCMS showed thedesired MS. The mixture was concentrated and purified by prep-TLC (SiO₂,petroleum ether:ethyl acetate=3:1, R_(f)=0.1) to afford 24e as a yellowsolid. ¹H NMR (400 MHz, MeOD-d₄) δ 8.62 (d, J=2.2 Hz, 1H), 8.45 (d,J=2.2 Hz, 1H), 7.84-7.80 (m, 2H), 7.30 (d, J=8.8 Hz, 2H), 4.64 (br s,1H), 3.80 (dd, J=6.8, 10.7 Hz, 1H), 3.39 (dd, J=4.2, 10.7 Hz, 1H), 2.80(dd, J=7.9, 17.1 Hz, 1H), 2.41 (dd, J=4.8, 17.1 Hz, 1H).

(S)-3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((5-oxopyrrolidin-3-yl)amino)benzamide(24f). To a mixture of(S)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-nitro-4-((5-oxopyrrolidin-3-yl)amino)benzamide(24e, 0.053 g, 0.102 mmol) in AcOH (1 mL) at 20° C. under N₂ was addedFe (56.95 mg, 1.02 mmol) in one portion, and the mixture was stirred at35° C. for 2 hours. LCMS showed the desired MS. The mixture was pouredinto sat. NaHCO₃ and extracted with ethyl acetate (5 mL×2). The combinedorganic layers were washed with brine (5 mL×2), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give 24f as a yellowsolid.

(S)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(5-oxopyrrolidin-3-yl)-1H-benzo[d]imidazole-5-carboxamide(24g). To a mixture of(S)-3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((5-oxopyrrolidin-3-yl)amino)benzamide(24f, 0.0358 g, 73.11 mmol) in CH(OMe)₃ (2 mL) at 20° C. under N₂ wasadded TsOH (1.26 mg, 7.31 umol) in one portion, and the mixture wasstirred at 20° C. for 30 min. LCMS showed the desired MS. The mixturewas extracted with ethyl acetate (3 mL×2), the combined organic layerswere washed with brine (5 mL×2), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo to obtain 24g as a yellow solid.

(S)-N-(4-(chlorodifluoromethoxy)phenyl)-1-(5-oxopyrrolidin-3-yl)-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide(24). To a mixture of(S)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(5-oxopyrrolidin-3-yl)-1H-benzo[d]imidazole-5-carboxamide(24g, 35.3 mg, 0.071 mmol) and pyrimidin-5-ylboronic acid (17.51 mg,0.141 mmol) in H₂O (0.1 mL) and dioxane (1 mL) under N₂ was addedPd(dppf)Cl₂ (5.17 mg, 7.06 umol), K₃PO₄ (29.99 mg, 0.141 mmol) in oneportion. The mixture was stirred at 100° C. for 12 hours. LCMS showedthe desired MS. The mixture was extracted with ethyl acetate (3 mL×3),the combined organic layers were washed with brine (5 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by prep-TLC (SiO₂, petroleum ether:ethyl acetate=1:5, R_(f)=0. 1) to afford the title compound 24 as a brown solid. MS masscalculated for [M+1]⁺ (C₂₃H₁₇ClF₂N₆O₃) requires m/z 499.1, LCMS foundm/z 499.1. ¹H NMR (400 MHz, DMSO-d₆) δ 9.39 (s, 1H), 8.90 (br s, 2H),8.49 (s, 1H), 8.40 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.78 (s, 1H),7.28 (br s, 2H), 6.12 (br s, 1H), 4.69 (br s, 1H), 3.65 (dd, J=6.5, 11.1Hz, 1H), 3.51 (br d, J=11.7 Hz, 1H), 2.82-2.60 (m, 2H).

Example 25N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1H-benzo[d]imidazole-5-carboxamide

N-(4-(chlorodifluoromethoxy)phenyl)-7-cyano-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(25b). A solution of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(10a, 0.15 g, 0.327 mmol), Zn(CN)₂ (57.60 mg, 0.491 mmol, 31.14 uL) andPd(PPh₃)₄ (18.89 mg, 0.016 mmol) in DMF (3 mL) were put into a microwavetube. The sealed tube was heated at 150° C. for 2 h under microwaveirradiation. LCMS showed the desired MS. The mixture was extracted withethyl acetate (2 mL×3), the combined organic layers were washed withbrine (5 mL×2), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by prep-TLC (SiO₂, petroleumether:ethyl acetate=0:1, R_(f)=0.67) to afford 1b as a white solid. ¹HNMR (400 MHz, CDCl₃-d) δ 8.52 (s, 1H), 8.30-8.21 (m, 2H), 8.09 (s, 1H),7.73 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.6 Hz, 2H), 5.32 (spt, J=6.7 Hz,1H), 1.72 (d, J=6.6 Hz, 6H).

(Z)-N-(4-(chlorodifluoromethoxy)phenyl)-7-(N′-hydroxycarbamimidoyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(25c). To a solution ofN-(4-(chlorodifluoromethoxy)phenyl)-7-cyano-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(25b, 20 mg, 0.049 mmol) in DMF (3 mL) was added NH₂OH.HCl (34.33 mg,0.494 mmol) and TEA (49.99 mg, 0.49 mmol, 68.76 uL) The mixture wasstirred at 75° C. for 12 hours. LCMS showed the desired MS. The aqueousphase was extracted with ethyl acetate (5 mL×3). The combined organiclayers were washed with brine (10 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by prep-TLC(SiO₂, petroleum ether:ethyl acetate=0:1, R_(f)=0.5) to afford 25c as awhite solid. MS mass calculated for [M+1]⁺ (C₁₉H₁₈ClF₂N₅O₃) requires m/z438.1, LCMS found m/z 438.3.

N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1H-benzo[d]imidazole-5-carboxamide(25). To a solution of(Z)-N-(4-(chlorodifluoromethoxy)phenyl)-7-(N′-hydroxycarbamimidoyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(25c, 0.02 g, 0.046 mmol) in THF (2 mL) under N₂ was addedbis(2,5-dioxopyrrolidin-1-yl) carbonate (15.21 mg, 0.059 mmol) and TEA(9.24 mg, 0.091 mmol, 12.72 uL). The mixture was stirred at 60° C. for12 hours. LCMS showed the desired MS. The aqueous phase was extractedwith ethyl acetate (3 mL×3), the combined organic layers were washedwith brine (5 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by prep-TLC (SiO₂, ethylacetate:methanol=10: 1, R_(f)=0.1) to yield the title compound 25 as ayellow solid. MS mass calculated for [M+1]⁺ (C₂₀H₁₆ClF₂N₅O₄) requiresm/z 464.1, LCMS found m/z 464.1; ¹H NMR (400 MHz, MeOD-d₄) δ 8.55 (s,1H), 8.43 (d, J=1.6 Hz, 1H), 8.09 (d, J=1.6 Hz, 1H), 7.85 (d, J=9.0 Hz,2H), 7.29 (d, J=8.9 Hz, 2H), 5.25 (td, J=6.6, 13.3 Hz, 1H), 1.53 (d,J=6.7 Hz, 6H).

Example 26N⁵-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5,7-dicarboxamide

N⁵-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5,7-dicarboxamide(26). To a solution ofN-(4-(chlorodifluoromethoxy)phenyl)-7-cyano-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(25b, 30 mg, 0.074 mmol) in DMSO (3 mL) was added NH₂OH.HCl (41.20 mg,0.593 mmol) and TEA (13.86 mg, 0.137 mmol) The mixture was stirred at80° C. for 12 hours. LCMS showed the desired MS. The aqueous phase wasextracted with ethyl acetate (5 mL×3). The combined organic layers werewashed with brine (10 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by prep-TLC (SiO₂,petroleum ether:ethyl acetate=0:1, R_(f)=0.5) to afford the titlecompound 26 as a white solid. MS mass calculated for [M+1]⁺(C₁₉H₁₇ClF₂N₄O₃) requires m/z 423.1, LCMS found m/z 423.0. ¹H NMR (400MHz, DMSO-d₆) δ 10.48 (s, 1H), 8.62 (s, 1H), 8.48 (d, J=1.6 Hz, 1H),8.27 (s, 1H), 7.98 (d, J=1.7 Hz, 1H), 7.97-7.94 (m, 2H), 7.78 (s, 1H),7.37 (d, J=9.0 Hz, 2H), 5.09 (quin, J=6.6 Hz, 1H), 1.52 (s, 3H), 1.50(s, 3H).

Example 27N-(4-(chlorodifluoromethoxy)phenyl)-3-isopropyl-4-(pyrimidin-5-yl)-3H-imidazo[4,5-c]pyridine-6-carboxamide

Methyl 4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-carboxylate(27b). To a solution of methyl4-chloro-3H-imidazo[4,5-c]pyridine-6-carboxylate (27a, 200 mg, 0.945mmol) and 2-iodopropane (482.01 mg, 2.84 mmol, 283.53 uL) in DMF (3 mL)was added K₂CO₃ (391.88 mg, 2.84 mmol). The mixture was stirred at 30°C. for 16 hr. LCMS showed 27a was consumed completely and desired MS wasdetected. The mixture was diluted with water (5 mL) and extracted withEtOAc (5 mL×3). The combined organic layers were washed with brine (5mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The residue was purified by prep-TLC (SiO₂, petroleumether:ethyl acetate=1:2) to afford 27c as a white solid. ¹H NMR (400MHz, CDCl₃-d) δ 8.54 (s, 1H), 8.30 (s, 1H), 5.60-5.42 (m, 1H), 4.04 (s,3H), 1.70 (d, J=6.7 Hz, 6H).

Methyl3-isopropyl-4-(pyrimidin-5-yl)-3H-imidazo[4,5-c]pyridine-6-carboxylate(27c). To a solution of methyl4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine-6-carboxylate (27b, 70mg, 0.276 mmol) and pyrimidin-5-ylboronic acid (68.38 mg, 0.552 mmol) indioxane (1 mL) and H₂O (0.1 mL) was added Pd(dppf)Cl₂ (20.19 mg, 27.59umol) and K₃PO₄ (175.71 mg, 0.828 mmol). The mixture was stirred at 110°C. for 16 hr under N₂. LCMS showed 27b was consumed completely anddesired MS was detected. The mixture was diluted with water (5 mL) andextracted with EtOAc (5 mL×3). The combined organic layers were washedwith brine (5 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by prep-TLC(SiO₂, ethyl acetate:methanol=10:1) to afford 27c as a white solid. ¹HNMR (400 MHz, MeOD-d₄) δ 9.36 (s, 1H), 9.13 (s, 2H), 8.82 (s, 1H), 8.56(s, 1H), 4.36-4.23 (m, 1H), 4.01 (s, 3H), 1.45 (d, J=6.6 Hz, 6H).

3-Isopropyl-4-(pyrimidin-5-yl)-3H-imidazo[4,5-c]pyridine-6-carboxylicacid (27d). To a solution of methyl3-isopropyl-4-(pyrimidin-5-yl)-3H-imidazo[4,5-c] pyridine-6-carboxylate(27c, 35 mg, 0.118 mmol) in THF (0.5 mL), MeOH (0.5 mL) and H₂O (0.25mL) was added LiOH.H₂O (9.88 mg, 0.235 mmol). The mixture was stirred at20° C. for 2 hr. TLC (ethyl acetate:methanol=10:1, R_(f)=0.0) showed 27cwas consumed completely and one major new spot with more polarity wasdetected. The mixture was concentrated in vacuo. Then the mixture wasadded to H₂O (3 mL) and the aqueous phase was acidified with aqueous HClto pH=5. The mixture was concentrated in vacuo. The product was used inthe next step without further purification. Compound 27d was obtained asa white solid. ¹H NMR (400 MHz, MeOD-d₄) δ 9.69 (s, 1H), 9.46 (s, 1H),9.22 (s, 2H), 8.80-8.67 (m, 1H), 4.42 (s, 1H), 1.50 (d, J=6.6 Hz, 6H).

N-(4-(chlorodifluoromethoxy)phenyl)-3-isopropyl-4-(pyrimidin-5-yl)-3H-imidazo[4,5-c]pyridine-6-carboxamide(27). To a solution of3-isopropyl-4-(pyrimidin-5-yl)-3H-imidazo[4,5-c]pyridine-6-carboxylicacid (27d, 32 mg, 0.113 mmol) and 1h (32.80 mg, 0.169 mmol) in DMF (2mL) was added DIEA (43.80 mg, 0.339 mmol, 59.03 uL) and HATU (51.54 mg,0.136 mmol). The mixture was stirred at 25° C. for 4 hr. LCMS showed 27dwas consumed completely and desired MS was detected. The mixture wasdiluted with water (5 mL) and extracted with EtOAc (5 mL×3). Thecombined organic layers were washed with brine (5 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-TLC (SiO₂, petroleum ether:ethyl acetate=0:1) to afford 27 as a white solid. MS mass calculated for[M+H]⁺ (C₂₁H₁₇O₂N₆ClF₂) requires m/z 459.1, LCMS found m/z 459.0. ¹H NMR(400 MHz, DMSO-d₆) δ 10.61 (s, 1H), 9.42 (s, 1H), 9.30 (s, 2H), 8.94 (s,1H), 8.50 (s, 1H), 8.05-7.95 (m, 2H), 7.37 (d, J=9.0 Hz, 2H), 4.38-4.09(m, 1H), 1.38 (d, J=6.7 Hz, 6H).

Example 28 General Procedure K(R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-fluoropropan-2-yl)-7-(1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide

This General Procedure K provides particular synthetic details asapplied to the title compound. Additional compounds can be preparedaccording to this method by varying the coupling reagents.

N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(R)-1-fluoropropan-2-yl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide(28b). To a solution of(R)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-fluoropropan-2-yl)-1H-benzo[d]imidazole-5-carboxamide(synthesized in a similar fashion to 15g; 28a, 30 mg, 0.057 mmol) and1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole(63.38 mg, 0.228 mmol) in DME (1.5 mL), EtOH (1.5 mL) and H₂O (0.3 mL)was added Pd(PPh₃)₂Cl₂ (4.00 mg, 5.70 umol), Na₂CO₃ (12.07 mg, 0.114mmol). The mixture was stirred at 80° C. for 2 hr. LCMS showed 28a wasconsumed completely and desired MS was detected. The mixture was dilutedwith water (5 mL) and extracted with EtOAc (5 mL×3). The combinedorganic layers were washed with brine (5 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-TLC (SiO₂, petroleum ether:ethylacetate=2:1) to afford 28b as a yellow solid.

(R)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(1-fluoropropan-2-yl)-7-(1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide(28). To a solution ofN-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-(R)-1-fluoropropan-2-yl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide(28b, 25 mg, 0.042 mmol) in DCM (1 mL) was added TFA (1.54 g, 13.51mmol, 1 mL). The mixture was stirred at 20° C. for 1 hr. LCMS showed 28bwas consumed completely and desired MS was detected. The mixture wasdiluted with water (5 mL) and extracted with EtOAc (5 mL×3). Thecombined organic layers were washed with brine (5 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-TLC (SiO₂, petroleumether:ethyl acetate=1:1) to afford 28 as a white solid. MS masscalculated for [M+H]⁺ (C₂₂H₁₇O₂N₅ClF₅) requires m/z 514.1, LCMS foundm/z 514.1. ¹H NMR (400 MHz, MeOD-d₄) δ 8.47 (d, J=1.3 Hz, 1H), 7.98 (d,J=1.7 Hz, 1H), 7.88 (br s, 1H), 7.87-7.81 (m, 2H), 7.44-7.15 (m, 3H),6.66 (d, J=2.2 Hz, 1H), 4.70-4.67 (m, 1H), 4.63-4.45 (m, 2H), 1.52 (brd, J=7.2 Hz, 3H).

Example 29N-(4-(chlorodifluoromethoxy)phenyl)-6-(pyrimidin-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]thiazine-8-carboxamide2,2-dioxide

6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]thiazine-8-carboxamide2,2-dioxide (29b). To a solution of6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]thiazine-8-carboxamide(synthesized in a similar fashion to 8g; 29a, 2 mg, 4.09 umol) inacetone (0.5 mL) and H₂O (0.1 mL) was added Oxone (5.03 mg, 8.18 umol).The mixture was stirred at 20° C. for 24 hr. TLC (petroleum ether:ethylacetate=0:1, R_(f)=0.77) indicated 29a was consumed completely and onemajor new spot with larger polarity was detected. The reaction wasquenched by sodium sulfide. The reaction mixture was concentrated underreduced pressure to remove acetone. The residue was diluted with H₂O (10mL) and extracted with EtOAc (10 mL×3). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified byprep-TLC (SiO₂, Petroleum ether:Ethyl acetate=0:1) to afford 29b as abrown solid. ¹H NMR (400 MHz, MeOD-d₄) δ 8.18 (d, J=1.5 Hz, 1H), 8.05(d, J=1.5 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.20 (br d, J=8.8 Hz, 2H),5.17-5.12 (m, 2H), 5.08 (s, 2H), 3.81-3.75 (m, 2H).

N-(4-(chlorodifluoromethoxy)phenyl)-6-(pyrimidin-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]thiazine-8-carboxamide2,2-dioxide (29). A mixture of6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]thiazine-8-carboxamide2,2-dioxide (29b, 6 mg, 0.012 mmol), pyrimidin-5-ylboronic acid (4.28mg, 0.035 mmol), Pd(dppf)Cl₂ (843.09 ug, 1.15 umol), K₃PO₄ (7.34 mg,0.035 mmol) in dioxane (1 mL) and H₂O (0.1 mL) was degassed and purgedwith N₂ three times, and then the mixture was stirred at 110° C. for 16hr under N₂ atmosphere. TLC (petroleum ether:ethyl acetate=0:1,R_(f)=0.3) indicated 29b was consumed completely and one major new spotwith larger polarity was detected. The reaction mixture was concentratedunder reduced pressure to remove dioxane. The residue was diluted withH₂O (1 mL) and extracted with ethyl acetate (1 mL×3). The combinedorganic layers were washed with brine (1 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-TLC (petroleum ether:ethyl acetate=0:1) toafford 29 as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H),9.33 (s, 1H), 9.09 (s, 2H), 8.45 (d, J=1.0 Hz, 1H), 7.91 (d, J=9.3 Hz,2H), 7.83 (d, J=1.5 Hz, 1H), 7.36 (d, J=8.8 Hz, 2H), 5.09 (s, 2H), 4.12(br t, J=5.9 Hz, 2H), 3.75 (br t, J=5.6 Hz, 2H).

Example 30 General Procedure LN-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide

This General Procedure L provides particular synthetic details asapplied to the title compound. Additional compounds can be preparedaccording to this method by varying the coupling reagents and/or thedeprotection reagents.

N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(trimethylsilyl)ethynyl)-1H-benzo[d]imidazole-5-carboxamide(30a). To a mixture of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(10a, 80 mg, 0.174 mmol) and ethynyl(trimethyl)silane (85.65 mg, 0.872mmol, 120.81 uL) in TEA (1 mL) was added CuI (3.32 mg, 0.017 mmol),Pd(PPh₃)₂Cl₂ (12.24 mg, 0.017 mmol) under N₂, the mixture was stirred at80° C. for 2 hours. LCMS showed desired MS. Water was added to thereaction mixture and the mixture was extracted with ethyl acetate (5mL×3). The combined organic layers were washed with brine (10 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by prep-TLC (SiO₂, petroleum ether:ethyl acetate=1:1, R_(f)=0.4) to give 30a as a white solid. ¹H NMR (400 MHz, CDCl₃-d) δ8.31 (s, 1H), 8.15 (br d, J=7.2 Hz, 2H), 8.00 (s, 1H), 7.75 (br d, J=8.9Hz, 2H), 7.30-7.27 (m, 2H), 5.65 (td, J=6.8, 13.4 Hz, 1H), 1.66 (d,J=6.7 Hz, 6H), 0.31 (s, 9H).

N-(4-(chlorodifluoromethoxy)phenyl)-7-ethynyl-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(30b). To a mixture ofN-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(trimethylsilyl)ethynyl)-1H-benzo[d]imidazole-5-carboxamide(30a, 70 mg, 0.147 mmol) in MeOH (2 mL) was added K₂CO₃ (40.65 mg, 0.294mmol, 2 eq). The mixture was stirred at 20° C. for 0.5 hours. TLC(petroleum ether:ethyl acetate=1: 1, R_(f)=0.5) inditcated 30a wasconsumed, and one major new spot with larger polarity was detected. Themixture was concentrated and extracted with ethyl acetate (5 mL×3). Thecombined organic layers were washed with brine (10 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by prep-TLC (SiO₂, petroleum ether:ethyl acetate=0:1,R_(f)=0.5) to give 30b as a yellow solid. ¹H NMR (400 MHz, CDCl₃-d) δ8.33 (d, J=1.6 Hz, 1H), 8.22-8.13 (m, 2H), 8.06 (d, J=1.5 Hz, 1H),7.78-7.72 (m, 2H), 7.29 (s, 2H), 5.68-5.49 (m, 1H), 3.44 (s, 1H), 1.66(d, J=6.7 Hz, 6H).

N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide(30c). To a mixture ofN-(4-(chlorodifluoromethoxy)phenyl)-7-ethynyl-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide (30b, 50 mg, 0.124 mmol) and1-(azidomethyl)-4-methoxy-benzene (22.23 mg, 0.136 mmol) in THF (1 mL),H₂O (1 mL) under N₂ was added CuSO_(4.) 5H₂O (1.55 mg, 6.19 umol) andsodium (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate(2.45 mg, 0.012 mmol). The mixture was stirred at 20° C. for 3 hours.LCMS showed the desired MS. The mixture was extracted with ethyl acetate(3 mL×3). The combined organic layers were washed with brine (5 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by prep-TLC (SiO₂, petroleum ether:ethylacetate=0:1, R_(f)=0.4) to give 30c as a yellow solid. ¹H NMR (400 MHz,CDCl₃-d) δ 8.28 (s, 1H), 8.20 (s, 1H), 8.09 (br s, 1H), 7.79-7.66 (m,4H), 7.32 (br d, J=8.4 Hz, 2H), 7.26-7.25 (m, 1H), 6.95 (d, J=8.4 Hz,2H), 5.59 (s, 2H), 5.11-5.02 (m, 1H), 3.84 (s, 3H), 1.36 (d, J=6.7 Hz,6H).

N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide(30). The mixture ofN-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazole-5-carboxamide(30c, 40 mg, 0.071 mmol) in TFA (3 mL) was stirred at 60° C. for 12hours. LCMS showed the desired MS. The mixture was concentrated andextracted with ethyl acetate (5 mL×3). The combined organic layers werewashed with brine (10 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by prep-TLC (SiO₂,petroleum ether:ethyl acetate=0:1, R_(f)=0.3) to give 30 as an off-whitesolid. MS mass calculated for [M+1]⁺ (C₂₀H₁₇ClF₂N₆O₂) requires m/z447.1, LCMS found m/z 447.0; ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H),8.62 (s, 1H), 8.48 (d, J=1.3 Hz, 1H), 8.31 (br s, 1H), 7.95 (d, J=9.0Hz, 2H), 7.85 (d, J=1.3 Hz, 1H), 7.36 (d, J=9.0 Hz, 2H), 4.63 (br s,1H), 1.32 (d, J=6.6 Hz, 6H).

Example 31 General Procedure MN-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyano-1H-pyrazol-3-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide

This General Procedure M provides particular synthetic details asapplied to the title compound. Additional compounds can be preparedaccording to this method by varying the coupling reagents and/or thedeprotection reagents.

N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(trimethylstannyl)-1H-benzo[d]imidazole-5-carboxamide(31a). To a mixture of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(10a, 94.7 mg, 0.206 mmol) and trimethyl(trimethylstannyl)stannane(270.57 mg, 0.826 mmol, 171.25 uL) in toluene (3 mL) under N₂ was addedPd(PPh₃)₄ (23.86 mg, 0.021 mmol). The mixture was stirred at 130° C. for12 hours. LCMS showed the desired MS. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate (5 mL×2). Thecombined organic layers were washed with brine (10 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by prep-TLC (SiO₂, petroleum ether:ethyl acetate=1:1,R_(f)=0.4) to give 31a as a colorless oil.

N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(31b). To a mixture ofN-(4-(chlorodifluoromethoxy)phenyl)-1-isopropyl-7-(trimethylstannyl)-1H-benzo[d]imidazole-5-carboxamide(31a, 50 mg, 0.92 mmol) and3-iodo-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carbonitrile (64.37mg, 0.184 mmol) in DMSO (3 mL) under N₂ was added Pd(PPh₃)₄ (10.65 mg,9.22 umol). The mixture was stirred at 100° C. for 12 hours. LCMS showedthe desired MS. The mixture was filtered and extracted with ethylacetate (3 mL×3) and water. The combined organic layers were washed withbrine (5 mL×2), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by prep-TLC (SiO₂, petroleumether:ethyl acetate=0:1, R_(f)=0.6) to afford 31b as a yellow oil. MSmass calculated for [M+1]⁺ (C₂₈H₃₁ClF₂N₆O₃Si) requires m/z 601.2, LCMSfound m/z 601.2.

N-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyano-1H-pyrazol-3-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(31). A mixture ofN-(4-(chlorodifluoromethoxy)phenyl)-7-(4-cyano-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(31b, 20 mg, 33.27 mmol) in TFA (0.5 mL) and DCM (0.5 mL) was stirred at20° C. for 2 hours. LCMS showed the desired MS. The mixture wasconcentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, petroleum ether:ethyl acetate=0:1, R_(f)=0.4) to give 31as a yellow solid. MS mass calculated for [M+1]⁺ (C₂₂H₁₇ClF₂N₆O₂)requires m/z 471.1, LCMS found m/z 471.0; ¹H NMR (400 MHz, DMSO-d₆) δ14.16 (br s, 1H), 10.52 (s, 1H), 8.90-8.78 (m, 1H), 8.68 (br s, 1H),8.59 (br s, 1H), 7.96 (d, J=9.0 Hz, 2H), 7.91 (s, 1H), 7.37 (br d, J=8.8Hz, 2H), 4.39 (br s, 1H), 1.36 (br d, J=6.7 Hz, 6H).

Example 32(R)-N⁸-(4-(chlorodifluoromethoxy)phenyl)-N⁶,4-dimethyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-6,8-dicarboxamide

(R)-methyl8-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-6-carboxylate(32b). To a solution of(R)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(synthesized in a similar fashion to 8g; 32a, 50 mg, 0.103 mmol) in MeOH(1 mL) and DMF (3 mL) under N₂ was added Pd(dppf)Cl₂ (15.03 mg, 0.021mmol), TEA (51.98 mg, 0.514 mmol, 71.50 uL), Pd(OAc)₂ (4.61 mg, 0.021mmol), Xantphos (11.89 mg, 0.021 mmol), PPh₃ (5.39 mg, 0.021 mmol andDPPP (8.47 mg, 0.021 mmol). The suspension was degassed under vacuum andpurged with CO several times. The mixture was stirred under CO (2 MPa)at 120° C. for 12 hours. LCMS showed desired ms was detected. Thereaction mixture was concentrated under reduced pressure. The residuewas diluted with H₂O (10 mL) and the mixture was extracted with EtOAc(10 mL×3). The combined organic layers were washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by prep-TLC (Sift, ethylacetate: petroleum ether=3:1, R_(f)=0.3) to afford the title compound32b as a brown solid. ¹H NMR (400 MHz, MeOD-d₄) δ 8.53-8.42 (m, 2H),7.88-7.81 (m, 2H), 7.30 (d, J=9.0 Hz, 2H), 5.41 (br dd, J=1.8, 6.5 Hz,1H), 5.18-4.95 (m, 2H), 4.24-4.18 (m, 1H), 4.12-4.08 (m, 1H), 4.04 (s,3H), 1.40 (d, J=6.5 Hz, 3H).

(R)-8-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-6-carboxylicacid (32c). To a solution of (R)-methyl8-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-6-carboxylate(32b, 22 mg, 0.047 mmol) in MeOH (1 mL), THF (1 mL) and H₂O (1 mL) wasadded LiOH.H₂O (7.93 mg, 0.189 mmol). The mixture was stirred at 50° C.for 5 hr. LCMS showed desired ms was detected. The reaction mixture wasconcentrated under reduced pressure to remove solvent. H₂O was added,and 1M HCl was added to the mixture drop-wise until pH=5. The mixturewas concentrated to give a crude product, which was used in next stepwithout purification. ¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (s, 1H), 8.55(d, J=1.7 Hz, 1H), 8.38 (d, J=1.7 Hz, 1H), 7.96 (d, J=9.2 Hz, 2H), 7.38(d, J=9.0 Hz, 2H), 5.38-5.26 (m, 1H), 5.16-4.90 (m, 2H), 4.29-3.98 (m,2H), 1.31 (d, J=6.5 Hz, 3H).

(R)-N⁸-(4-(chlorodifluoromethoxy)phenyl)-N⁶,4-dimethyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-6,8-dicarboxamide(32). To a solution of(R)-8-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-6-carboxylicacid (32c, 21 mg, 0.046 mmol) and methanamine hydrochloride (31.38 mg,0.465 mmol) in DMF (2 mL) was added HATU (53.02 mg, 0.139 umol) and DIEA(48.06 mg, 0.372 mmol, 64.77 uL). The mixture was stirred at 20° C. for24 hr. LCMS showed desired ms was detected. The reaction mixture wasconcentrated under reduced pressure to remove solvent. The residue wasdiluted with H₂O (5 mL) and extracted with EtOAc (5 mL×3). The combinedorganic layers were washed with brine (5 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-TLC (SiO₂, petroleum ether:ethylacetate=0:1, R_(f)=0.60) to afford the title compound 32 as a whitesolid. MS mass calculated for [M+1]⁺ (C₂₁H₁₉ClF₂N₄O₄) requires m/z465.1, LCMS found m/z 465.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H),8.85-8.73 (m, 1H), 8.42 (d, J=1.6 Hz, 1H), 8.04-7.90 (m, 3H), 7.37 (d,J=9.0 Hz, 2H), 5.13-4.89 (m, 3H), 4.18-3.95 (m, 2H), 2.87 (d, J=4.6 Hz,3H), 1.28 (d, J=6.5 Hz, 3H).

Example 33 General Procedure N(R)-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-5-(1H-pyrazol-5-yl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide

This General Procedure N provides particular synthetic details asapplied to the title compound. Additional compounds can be preparedaccording to this method by varying the coupling reagents.

(R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole-7-carboxamide(33b) &(R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide(33c). A solution of(R)-1-(3-amino-5-bromo-4-((1-hydroxypropan-2-yl)amino)phenyl)-2-(4-(chlorodifluoromethoxy)phenyl)ethanone(synthesized in a similar fashion to 6c; 33a, 330 mg, 0.71 mmol) anddi(imidazol-1-yl)methane thione (379.68 mg, 2.13 mmol) in THF (15 mL)was stirred at 15° C. for 16 hr. TLC (petroleum ether:ethyl acetate=0:1,R_(f)=0.6) showed two new spots were generated. LCMS showed two peakswith with MS of 33b and 33c was detected. The mixture was concentrated.The crude product was purified by silica gel column chromatography(petroleum ether:ethyl acetate=3:1˜0:1) to give 33b as a yellow solid.¹H NMR (400 MHz, CDCl₃-d) δ 8.14 (s, 1H), 7.99 (d, J=1.5 Hz, 1H), 7.93(d, J=1.5 Hz, 1H), 7.77-7.69 (m, 2H), 7.28 (br s, 1H), 7.26 (br s, 1H),5.39 (quin, J=6.5 Hz, 1H), 4.35-4.24 (m, 1H), 3.48 (d, J=11.1 Hz, 1H),1.57 (d, J=6.4 Hz, 3H). A batch of crude product was further purified bysilica gel column chromatography (petroleum ether:ethyl acetate=3:1˜0:1)to give 33c as a colourless solid. ¹H NMR (400 MHz, CDCl₃-d) δ 8.49 (s,1H), 8.02 (d, J=1.3 Hz, 1H), 7.92 (d, J=1.5 Hz, 1H), 7.79-7.72 (m, 2H),7.28 (br s, 1H), 7.26 (s, 1H), 5.37 (quin, J=6.6 Hz, 1H), 4.26 (dd,J=7.2, 11.1 Hz, 1H), 4.13 (q, J=7.2 Hz, 1H), 3.46 (d, J=11.0 Hz, 1H),1.56 (d, J=6.4 Hz, 3H).

(R)-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-5-(1H-pyrazol-5-yl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide(33). A mixture of(R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide(33c, 20 mg, 0.042 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (32.84 mg,0.169 mmol), K₃PO₄ (26.94 mg, 0.127 mmol), Pd(dppf)CL₂ (6.19 mg, 8.46umol) and Boc₂O (4.62 mg, 0.021 umol, 4.86 uL) in dioxane (2 mL) and H₂O(0.2 mL) was degassed and purged with N₂ 3 times. The mixture wasstirred at 110° C. for 16 hr under N₂ atmosphere. LCMS showed 33cremained. To this mixture was added5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24.63 mg,0.127 mmol), K₃PO₄ (17.96 mg, 0.085 mmol) and Pd(dppf)Cl₂ (6.19 mg, 8.46umol). The mixture was stirred at 110° C. for 4 hr under N₂ atmosphere.LCMS showed a peak with desired MS was detected. TLC (ethylacetate:methanol=10:1, R_(f)=0.48) showed a new spot was generated. Thereaction mixture was concentrated and H₂O (10 mL) was added. The mixturewas extracted with ethyl acetate (20 mL×3). The combined organic layerswere washed with brine (10 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The crude product was purified by prep-TLC(ethyl acetate:methanol=10:1, R_(f)=0.48) to give a crude product, whichwas further purified by prep-TLC (DCM:methanol=10:1, R_(f)=0.5) to give33 as a white solid. MS mass calculated for [M+1]⁺ (C₂₁H₁₆ClF₂N₅O₃)requires m/z 460.1, LCMS found m/z 460.1. ¹H NMR (400 MHz, MeOD-d₄) δ8.00 (br d, J=9.7 Hz, 2H), 7.88-7.81 (m, 3H), 7.29 (d, J=8.8 Hz, 2H),6.79 (br s, 1H), 5.29 (br d, J=7.9 Hz, 2H), 4.79 (br d, J=5.7 Hz, 1H),1.00 (br d, J=4.9 Hz, 3H).

Example 34 General Procedure O(R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-(hydroxymethyl)-6-(1H-pyrazol-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide

This General Procedure O provides particular synthetic details asapplied to the title compound. Additional compounds can be preparedaccording to this method by varying the coupling reagents and/ordeprotection reagents.

(R)-methyl6-bromo-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxylate(34b). A solution of (R)-methyl4-((benzyloxy)methyl)-6-bromo-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxylate(synthesized in a similar fashion to 8e; 34a, 1.2 g, 2.78 mmol) in TFA(10 mL) was stirred at 75° C. for 16 hours. LCMS showed the desired MS.The mixture was concentrated to afford 34b as a yellow oil. MS masscalculated for [M+1]⁺ (C₁₃H₁₃BrN₂O₄) requires m/z 341.0, LCMS found m/z341.0.

(R)-6-bromo-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxylicacid (34c). To a solution of (R)-methyl6-bromo-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxylate(34b, 0.95 g, 2.78 mmol) in THF (5 mL), MeOH (5 mL) and H₂O (1 mL) wasadded LiOH.H₂O (233.71 mg, 5.57 mmol). The mixture was stirred at 50° C.for 1 hour. LCMS showed the desired MS. The mixture was concentrated andthe residue was dissolved in water (5 mL). The suspension was extractedwith ethyl acetate (10 mL×2) and to the water phase was added HCl (1M)drop-wise until pH=3. The precipitated solid was collected by filtrationand dried to afford 34c as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.12 (s, 1H), 7.95 (d, J=1.2 Hz, 1H), 5.45-5.36 (m, 1H), 5.13-5.05 (m,1H), 4.97-4.88 (m, 1H), 4.38 (d, J=12.1 Hz, 1H), 4.02 (br d, J=11.9 Hz,1H), 3.90 (br d, J=10.1 Hz, 1H), 3.67 (dt, J=5.9, 10.1 Hz, 1H).

(R)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(34d). To a mixture of(R)-6-bromo-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxylicacid (34c, 0.85 g, 2.60 mmol) and 4-(chlorodifluoromethoxy)aniline (1h,528.13 mg, 2.73 mmol) in pyridine (10 mL) was added HATU (1.48 g, 3.90mmol). The mixture was stirred at 40° C. for 6 hours. LCMS showed thedesired MS. The reaction mixture was poured into water (30 mL) and themixture was extracted with ethyl acetate (50 mL×3). The combined organiclayers were washed with brine (100 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=100:1 to 0:1,R_(f)=0.4) give 34d as a white solid. Mass calculated for [M+1]⁺(C₁₉H₁₅BrClF₂N₃O₄) requires m/z 502.0, LCMS found m/z 502.0; ¹H NMR (400MHz, CDCl₃-d) δ 8.10 (brs, 1H), 8.04 (d, J=1.3 Hz, 1H), 7.98 (d, J=1.3Hz, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.28 (s, 2H), 5.16 (d, J=16.5 Hz, 1H),5.12-5.06 (m, 1H), 4.94 (d, J=16.3 Hz, 1H), 4.57 (d, J=12.3 Hz, 1H),4.22 (dd, J=2.8, 10.5 Hz, 1H), 4.15-4.08 (m, 2H), 2.27 (br s, 1H).

(R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-(hydroxymethyl)-6-(1H-pyrazol-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamid(34). To a mixture of(R)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(34d, 0.5 g, 0.995 mmol) and pyrimidin-5-ylboronic acid (369.72 mg, 2.98mmol) in dioxane (5 mL), H₂O (0.5 mL) was added K₃PO₄ (422.27 mg, 1.99mmol), Pd(dppf)Cl₂ (72.78 mg, 0.099 mmol), (Boc)₂O (217.08 mg, 0.995mmol, 228.51 uL) under N₂. The mixture was stirred at 110° C. for 16hours. LCMS showed the desired MS. The mixture was filtered andconcentrated. The residue was purified by column chromatography (SiO₂,petroleum ether:ethyl acetate=100:1 to 0:1, R_(f)=0.3) to give 34 as ayellow solid. Mass calculated for [M+1]⁺ (C₂₂H₁₈ClF₂N₅O₄) requires m/z490.1, LCMS found m/z 490.1; ¹H NMR (400 MHz, MeOD-d₄) δ 8.29 (br s,1H), 7.95 (s, 1H), 7.84 (br d, J=8.6 Hz, 3H), 7.30 (br d, J=8.8 Hz, 2H),6.71 (br s, 1H), 5.17-4.93 (m, 2H), 4.37 (br d, J=12.2 Hz, 1H), 4.08 (brd, J=11.0 Hz, 1H), 3.60 (s, 1H), 3.53-3.40 (m, 2H).

Example 35(S)-N-(4-(chlorodifluoromethoxy)phenyl)-4-(fluoromethyl)-6-(1H-pyrazol-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide

(S)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(fluoromethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(35a). To a mixture of(R)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(hydroxymethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(34d, 0.03 g, 0.06 mmol) in DCM (2 mL) at 0° C. under N₂ was added DAST(19.24 mg, 0.119 mmol, 15.77 uL). The mixture was stirred at 25° C. for8 hours. LCMS showed the desired MS. The crude product was purified byprep-TLC (SiO₂, petroleum ether:ethyl acetate=0:1, R_(f)=0.6) to give35a as a white solid. MS mass calculated for [M+1]⁺ (C₁₉H₁₄BrClF₃N₃O₃)requires m/z 504.0, LCMS found m/z 504.0.

(S)-N-(4-(chlorodifluoromethoxy)phenyl)-4-(fluoromethyl)-6-(1H-pyrazol-5-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(35). To a mixture of(S)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(fluoromethyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(35a, 10 mg, 0.02 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.53 mg,0.059 mmol) in dioxane (2 mL) and H₂O (0.2 mL) was added (Boc)₂O (4.32mg, 0.02 mmol, 4.55 uL), Pd(dppf)Cl₂ (1.45 mg, 1.98 umol), K₃PO₄ (12.62mg, 0.059 mmol). The mixture was stirred at 110° C. for 12 hours. LCMSshowed the desired MS. The mixture was filtered and concentrated. Theresidue was purified by prep-HPLC (column: Nano-micro Kromasil C18100*30 mm 5 um; mobile phase: [water(0.1%TFA)-ACN];B %: 36%-53%,10 min)to give 35 as a white solid. MS mass calculated for [M+1]⁺(C₂₂H₁₇ClF₃N₅O₃) requires m/z 492.1, LCMS found m/z 492.1; ¹H NMR (400MHz, CDCl₃-d) δ 8.21 (br s, 1H), 8.11 (br s, 1H), 7.92 (s, 1H),7.80-7.73 (m, 3H), 7.29 (s, 2H), 6.68 (br s, 1H), 5.33 (br s, 1H), 5.18(br d, J=16.1 Hz, 1H), 5.05-4.92 (m, 1H), 4.49-4.27 (m, 2H), 4.17-3.98(m, 2H).

Example 36(R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxyazetidin-1-yl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide

(R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxyazetidin-1-yl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(36). To a mixture of(R)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(32a, 20 mg, 0.041 mmol), azetidin-3-ol (36a, 15.02 mg, 0.205 mmol) inTHF (0.8 mL) under N₂ was added BrettPhos Pd G3 (3.73 mg, 4.11 umol) andt-BuONa (2 M, 41.09 uL). The mixture was stirred at 100° C. for 16 hr ina sealed tube. LCMS showed a peak with desired MS. TLC (ethylacetate:methanol=10:1, R_(f)=0.47) showed a new spot was generated. Thereaction mixture was concentrated. The crude product was purified byprep-TLC (ethyl acetate: methanol=10:1, R_(f)=0.47), which was furtherpurified by prep-HPLC (Column: Waters Xbridge 150*25 5 u; mobile phase:[water (10 mM NH₄HCO₃)-ACN]; B %: 25%-55%, 7 min) to afford 36 as awhite solid. MS mass calculated for [M+1]⁺ (C₂₂H₂₁ClF₂N₄O₄) requires m/z479.1, LCMS found m/z 479.1; ¹H NMR (400 MHz, MeOD-d₄) δ 7.91 (d, J=1.3Hz, 1H), 7.86-7.81 (m, 2H), 7.54 (d, J=1.3 Hz, 1H), 7.30 (d, J=9.0 Hz,2H), 5.05-4.99 (m, 2H), 4.95 (s, 1H), 4.72-4.65 (m, 1H), 4.36 (br t,J=6.5 Hz, 1H), 4.22 (dd, J=3.3, 12.0 Hz, 1H), 4.10-4.04 (m, 2H),4.02-3.96 (m, 1H), 3.54 (t, J=6.3 Hz, 1H), 1.56 (d, J=6.4 Hz, 3H).

Example 37N-(4-(chlorodifluoromethoxy)phenyl)-9-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide

Methyl9-bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(37b). To a solution of methyl3-amino-5-bromo-4-(piperidin-1-yl)benzoate (synthesized in a similarfashion to 1d; 37a, 160 mg, 0.511 mmol) in formic acid (3 mL) was addedH₂O₂ (521.32 mg, 4.60 mmol, 441.79 uL, 30% purity). The mixture washeated at reflux temperature for 40 min. LCMS showed 37a was consumedcompletely and one main peak with desired mass was detected. TLC(petroleum ether:ethyl acetate=2:1, R_(f)=0.20) indicated the reactantwas consumed completely and one new spot formed. The mixture wasconcentrated under reduce pressure. The residue was dissolved in ethylacetate (30 mL). The organic layers were washed with saturated aq.NaHCO₃ (10 mL×3), dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by prep-TLC (petroleum ether:ethylacetate=2:1, R_(f)=0.20) to afford 37b as a white solid. ¹H NMR (400MHz, CDCl₃-d) δ 8.24-8.18 (m, 1H), 8.00 (d, J=1.3 Hz, 1H), 4.61-4.55 (m,2H), 3.87 (s, 3H), 3.09-3.01 (m, 2H), 2.10-2.03 (m, 2H), 1.99-1.89 (m,2H).

9-Bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylicacid (37c). To a solution of methyl9-bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(37b, 50 mg, 0.162 mmol) in MeOH (1 mL), H₂O (1 mL) and THF (1 mL) wasadded LiOH.H₂O (13.57 mg, 0.323 mmol). The mixture was stirred at 50° C.for 2 hr. LCMS showed 37b was consumed completely and one main peak withdesired mass was detected. The mixture was concentrated to remove THFand MeOH. Then 1M HCl in water was added to the reaction mixturedrop-wise until pH=5. The suspension was filtered, and the filter cakewas washed with H₂O (1 mL) and dried to afford 37 as white solid. ¹H NMR(400 MHz, CDCl₃-d) δ 8.34 (d, J=1.3 Hz, 1H), 8.31 (d, J=1.2 Hz, 1H),4.87-4.84 (m, 2H), 3.32-3.32 (m, 2H), 2.28-2.06 (m, 4H).

9-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(37d). To a solution of9-bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylicacid (37c, 47 mg, 0.159 mmol) in DMF (4 mL) was added HATU (72.66 mg,0.191 mmol), DIEA (61.75 mg, 0.478 mmol, 83.22 uL) and4-(chlorodifluoromethoxy)aniline (1h, 61.66 mg, 0.319 umol). The mixturewas stirred at 15° C. for 16 hr. LCMS showed 37c was consumed completelyand one main peak with desired mass was detected. TLC (ethylacetate:methanol=10:1, R_(f)=0.36) indicated 37c was consumed completelyand one new spot formed. H₂O (20 mL) was added to the mixture. Themixture was extracted with ethyl acetate (10 mL×3). The combined organiclayers were washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by prep-TLC (ethylacetate:methanol=10:1, R_(f)=0.36) to afford 37d as a white oil. ¹H NMR(400 MHz, CDCl₃-d) δ 8.01 (d, J=1.5 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H),7.75-7.67 (m, 2H), 7.15 (d, J=8.8 Hz, 2H), 4.60 (t, J=6.2 Hz, 2H), 3.02(t, J=6.5 Hz, 2H), 2.09-2.04 (m, 2H), 1.97-1.88 (m, 2H).

N-(4-(chlorodifluoromethoxy)phenyl)-9-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(37). A mixture of9-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(37d, 20 mg, 0.042 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24.73 mg,0.127 mmol), Pd(dppf)Cl₂ (3.11 mg, 4.25 umol) and K₃PO₄ (27.06 mg, 0.127mmol) in dioxane (1 mL) and H₂O (0.1 mL) was degassed and purged with N₂3 times. The mixture was stirred at 110° C. for 16 hr under N₂atmosphere. LCMS showed 37d was consumed completely and one main peakwith desired mass was detected. TLC (dichloromethane:methanol=10:1,R_(f)=0.44) indicated 37d was consumed completely and one new spotformed. The mixture was concentrated and H₂O (10 mL) was added. Themixture was extracted with ethyl acetate (10 mL×3). The combined organiclayers were washed with brine (10 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified byprep-TLC (dichloromethane:methanol=10:1, R_(f)=0.30) to afford 37 as awhite solid. MS mass calculated for [M+1]⁺ (C₂₂H₁₈ClF₂N₅O₂) requires m/z458.1, LCMS found m/z 458.1; ¹H NMR (400 MHz, MeOD-d₄) δ 8.26-8.23 (m,1H), 7.86-7.81 (m, 4H), 7.29 (d, 2H, J=9.0 Hz), 6.62 (s, 1H), 3.86 (brs, 2H), 3.12 (br t, 2H, J=6.1 Hz), 1.99 (br s, 4H).

Example 38 General Procedure P(R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-9-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide

The title compound was prepared according to Scheme 10. This GeneralProcedure P exemplifies Scheme 10 and provides particular syntheticdetails as applied to the title compound.

(R)-methyl9-bromo-2-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(39b) and (R)-methyl9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(38c). A solution of methyl (R)-methyl3-bromo-4-(3-hydroxypiperidin-1-yl)-5-nitrobenzoate (synthesized in asimilar fashion to 1d; 38a, 100 mg, 0.278 mmol) in AcOH (3 mL) wasstirred at 30° C. Iron powder (155.48 mg, 2.78 mmol) was added slowly tothe reaction mixture portion-wise over 32 hrs. TLC (ethylacetate:methanol=10:1, R_(f)=0.37) showed two new spots were generated.LCMS showed two peaks with desired MS was detected. The reaction mixturewas filtered, and the filtrate was partitioned between ethyl acetate (50mL) and H₂O (50 mL). The separated organic layer was washed with water(50 mL×3), and then washed with saturated NaHCO₃ aqueous (30 mL×3),dried over Na₂SO₄ and evaporated to dryness. The crude product waspurified by prep-TLC (ethyl acetate:methanol=10:1, R_(f)=0.3) to give38b as a yellow solid. ¹H NMR (400 MHz, MeOD-d₄) δ 8.16 (d, J=1.1 Hz,1H), 8.02 (d, J=1.3 Hz, 1H), 4.82-4.74 (m, 1H), 4.69-4.61 (m, 1H),4.50-4.42 (m, 1H), 3.93 (s, 3H), 3.25 (dd, J=6.7, 9.8 Hz, 1H), 3.13-3.04(m, 1H), 2.20-2.09 (m, 2H). The crude product was purified by prep-TLC(ethyl acetate:methanol=10:1, R_(f)=0.37) to give 38c was obtained as ayellow solid. ¹H NMR (400 MHz, MeOD-d₄) δ 8.27 (d, J=0.9 Hz, 1H), 8.07(d, J=1.1 Hz, 1H), 4.97 (t, J=5.4 Hz, 1H), 4.79-4.70 (m, 1H), 4.65-4.52(m, 1H), 3.94 (s, 3H), 2.38 (br dd, J=6.8, 13.5 Hz, 1H), 2.26-2.04 (m,3H).

(R)-9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylicacid (38d). To a solution of (R)-methyl9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(38c, 25 mg, 0.077 mmol) in MeOH (1 mL), H₂O (1 mL) and THF (1 mL) wasadded LiOH.H₂O (6.45 mg, 0.154 mmol). The mixture stirred at 50° C. for2 hr. TLC (ethyl acetate:methanol=10:1, R_(f)=0.0) showed a new spot wasgenerated. The mixture was concentrated to remove solvent. To themixture 1M HCl was added to the reaction mixture drop-wise until pH=5.The mixture was concentrated, and the crude product was used into thenext step further without purification.

(R)-9-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(38e). To a solution of(R)-9-bromo-4-hydroxy1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylicacid (38d, 30 mg, 0.096 mmol) in DMF (2 mL) was added HATU (54.99 mg,0.145 mmol), DIEA (124.62 mg, 0.964 mmol, 167.95 uL) and4-[chloro(difluoro)methoxy]aniline (1h, 28.00 mg, 0.145 mmol). Themixture was stirred at 15° C. for 16 hr. TLC (ethylacetate:methanol=10:1, R_(f)=0.3) indicated a new spot was generated.LCMS showed a peak with desired MS was detected. The mixture wasquenched with water (20 mL) and the mixture was extracted with ethylacetate (30 mL×3). The combined organic layers were washed with brine(20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by prep-TLC (ethylacetate:methanol=10:1, R_(f)=0.3) to give 38e as a yellow solid.

(R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-9-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide (38). A mixture of(R)-9-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(38e, 15 mg, 0.031 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (17.94 mg,0.092 mmol), Pd(dppf)Cl₂ (4.51 mg, 6.16 umol), K₃PO₄ (19.63 mg, 0.092mmol) in dioxane (2 mL) and H₂O (0.2 mL) was degassed and purged with N₂3 times. The mixture was stirred at 120° C. for 16 hr under N₂atmosphere. TLC (ethyl acetate: methanol=5:1, R_(f)=0.2) showed a newspot was generated. LCMS showed a peak with desired MS was detected. Themixture was concentrated. The crude product was purified by prep-HPLC(Column:Luna C18 100*30 5 u; mobile phase: [water (0.225%FA)-ACN]; B %:1%-50%, 12 min) to give 38 as a white solid. Mass calculated for [M+1]⁺(C₂₂H₁₈ClF₂N₅O₂) requires m/z 474.1, LCMS found m/z 474.1; ¹H NMR (400MHz, MeOD-d₄) δ 8.34 (s, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.87-7.82 (m, 3H),7.29 (d, J=8.9 Hz, 2H), 6.62 (d, J=2.1 Hz, 1H), 5.01 (t, J=5.1 Hz, 1H),3.95-3.76 (m, 2H), 2.19 (br d, J=6.7 Hz, 2H), 2.07-1.88 (m, 2H).

Example 39 General Procedure Q(R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(4-hydroxypyridin-2-yl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide

This General Procedure Q provides particular synthetic details asapplied to the title compound. Additional compounds can be preparedaccording to this method by varying the coupling reagents.

(R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(39a). A mixture of(R)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(32a, 200 mg, 0.411 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(939.17 mg, 3.70 mmol), Pd(OAc)₂ (9.23 mg, 0.041 mmol), XPhos (48.97 mg,0.103 mmol) and K₃PO₄ (261.68 mg, 1.23 mmol) in dioxane (6.2 mL) wasdegassed and purged with N₂ 3 times. The mixture was stirred at 60° C.for 16 hr under N₂ atmosphere under microwave. LCMS showed desired MSwas detected. The reaction mixture was concentrated under reducedpressure to remove solvent. The residue was purified by prep-TLC (SiO₂,petroleum ether:ethyl acetate=0:1) to afford 39a as a white solid.

(R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(4-hydroxypyridin-2-yl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(39). A mixture of(R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(39a, 5 mg, 9.37 umol), 2-bromopyridin-4-ol (2.44 mg, 0.014 mmol),Pd(dppf)Cl₂ (685.43 ug, 9.37 umol), Na₂CO₃ (2.98 mg, 0.028 mmol) in DME(0.5 mL) and H₂O (0.1 mL) was degassed and purged with N₂ 3 times. Themixture was stirred at 120° C. for 1 hr under N₂ atmosphere in amicrowave reactor. LCMS showed 39a was consumed completely and desiredMS were detected. The reaction mixture was concentrated under reducedpressure to remove solvent. The residue was purified by prep-HPLC(column: Xtimate C18 150*25 mm*5 um; mobile phase: [water(10 mMNH₄HCO₃)-ACN];B %: 25%-55%,10 min) to afford 39 as a white solid. MSmass calculated for [M+1]⁺ (C₂₄H₁₉ClF₂N₄O₄) requires m/z 501.1, LCMSfound m/z 501.1; ¹H NMR (400 MHz, MeOD-d₄) δ 8.41 (d, J=1.5 Hz, 1H),8.03 (br d, J=6.8 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 7.88-7.81 (m, 2H),7.29 (d, J=8.8 Hz, 2H), 6.79 (br s, 1H), 6.68 (br d, J=6.8 Hz, 1H),5.15-4.96 (m, 2H), 4.46 (br s, 1H), 4.13 (br d, J=3.1 Hz, 1H), 3.99 (d,J=12.3 Hz, 1H), 1.14 (d, J=6.6 Hz, 3H).

Example 40 General Procedure R(S)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(1-hydroxyethyl)-1-isopropyl-7-(1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide

This General Procedure R provides particular synthetic details asapplied to the title compound. Additional compounds can be preparedaccording to this method by varying the coupling reagents.

(S)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-(2-hydroxypropanamido)-4-(isopropylamino)benzamide(40a). To a solution of3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(isopropylamino)benzamide(9a, 350 mg, 0.78 mmol) in DCM (1 mL) was added DIEA (302.44 mg, 2.34mmol, 407.60 uL), (2S)-2-hydroxypropanoic acid (140.53 mg, 1.56 mmol,116.14 uL) and 2-chloro-1,3-dimethylimidazolinium chloride (158.24 mg,0.936 mmol). The mixture was stirred at 15° C. for 4hr. TLC (petroleumether:Ethyl acetate=1:1, R_(f)=0.45) indicated 9a was consumedcompletely and one major new spot with larger polarity was detected.LCMS detected the desired MS. The reaction mixture was diluted with H₂O(20 mL) and extracted with DCM (10 mL×3). The combined organic layerswere washed with brine (30 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-TLC (SiO₂, petroleum ether:ethyl acetate=1:1) to afford40b as a white solid. ¹H NMR (400 MHz, MeOD-d₄) δ 8.53 (d, J=2.4 Hz,1H), 7.99 (d, J=2.0 Hz, 1H), 7.83-7.80 (m, 2H), 7.30 (br d, J=9.3 Hz,2H), 4.34 (q, J=6.8 Hz, 1H), 3.56 (td, J=6.4, 12.7 Hz, 1H), 1.49 (d,J=6.8 Hz, 3H), 1.24 (d, J=6.4 Hz, 6H).

(S)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(1-hydroxyethyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(40b). To a solution of(S)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-(2-hydroxypropanamido)-4-(isopropylamino)benzamide(40a, 40 mg, 0.077 mmol) in toluene (1 mL) was added4-methylbenzenesulfonic acid (2.65 mg, 0.015 mmol). The mixture wasstirred at 100° C. for 4 hr. TLC (petroleum ether:ethyl acetate=1:1,R_(f)=0.15) indicated 40a was consumed completely and one major new spotwith larger polarity was detected. LCMS detected the desired MS. Theresidue was diluted with H₂O (20 mL) and extracted with DCM (10 mL×3).The combined organic layers were washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-TLC (SiO₂, petroleumether:ethyl acetate=1:1) to afford 40b as a white solid. ¹H NMR (400MHz, MeOD-d₄) δ 8.29 (s, 1H), 8.14 (br s, 1H), 7.86 (d, J=9.3 Hz, 2H),7.32 (br d, J=9.3 Hz, 2H), 4.92-4.92 (m, 1H), 4.87-4.86 (m, 1H), 1.91(br s, 3H), 1.76 (br d, J=6.4 Hz, 6H).

(S)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(1-hydroxyethyl)-1-isopropyl-7-(1H-pyrazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide(40). A mixture of(S)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(1-hydroxyethyl)-1-isopropyl-1H-benzo[d]imidazole-5-carboxamide(40b, 10 mg, 0.02 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.58 mg,0.06 mmol), K₃PO₄ (12.67 mg, 0.06 mmol), Pd(dppf)Cl₂ (1.46 mg, 1.99umol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(11.58 mg, 0.06 mmol) in dioxane (1 mL) and H₂O (0.1 mL) was degassedand purged with N₂ 3 times. The mixture was stirred at 115° C. for 4 hrunder N₂ atmosphere. TLC (ethyl acetate:methanol=20:1, R_(f)=0.24)indicated 40b was consumed completely and one major new spot with largerpolarity was detected. LCMS detected the desired MS. The reactionmixture was concentrated under reduced pressure to remove solvent. Theresidue was diluted with H₂O (20 mL) and extracted with ethyl acetate(10 mL×3). The combined organic layers were washed with brine (30 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by prep-TLC (ethylacetate:methanol=20:1) to afford 40 as a white solid. Mass calculatedfor [M+1]⁺ (C₂₃H₂₂ClF₂N₅O₃) requires m/z 490.1, LCMS found m/z 490.1; ¹HNMR (400 MHz, MeOD-d₄) 6 8.34 (br s, 1H), 7.92-7.79 (m, 4H), 7.29 (d,J=9.3 Hz, 2H), 6.61 (d, J=2.0 Hz, 1H), 5.29 (q, J=6.0 Hz, 1H), 4.76 (brs, 1H), 1.73 (d, J=6.4 Hz, 3H), 1.45 (dd, J=7.1, 12.0 Hz, 6H).

Example 41(R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-6-(pyrrolidin-1-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide

(R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-6-(pyrrolidin-1-yl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(41). A mixture of(R)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-methyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine-8-carboxamide(32a, 50 mg, 0.103 mmol), pyrrolidine (438.39 mg, 6.16 mmol, 514.54 uL),(Bu4NCuI₂)₂ (23.00 mg, 0.021 mmol), Cs₂CO₃ (66.95 mg, 0.205 mmol) and3,4,7,8-tetramethyl-1,10-phenanthroline (2.43 mg, 0.01 mmol) in dioxane(2 mL) was degassed and purged with N₂ 3 times. The mixture was stirredat 120° C. for 16 hr under N₂ atmosphere. LCMS showed desired mass wasdetected. The reaction mixture was filtered and concentrated underreduced pressure to give a residue. The residue was purified by prep-TLC(SiO₂, ethyl acetate: methanol=20:1) to afford 41 as a white solid. Masscalculated for [M+1]⁺ (C₂₃H₂₃ClF₂N₄O₃) requires m/z 477.1, LCMS foundm/z 477.1. ¹H NMR (400 MHz, CDCl₃-d) 8.61 (s, 1H), 7.74 (d, J=9.0 Hz,2H), 7.25 (s, 1H), 7.22 (d, J=6.6 Hz, 2H), 5.16-4.92 (m, 2H), 4.47 (brs, 1H), 4.15-4.00 (m, 2H), 3.26 (br s, 4H), 2.12 (br s, 4H), 1.63 (d,J=6.6 Hz, 3H).

Example 42 General Procedure S(R)-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-5-(pyridazin-3-yl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide

This General Procedure S provides particular synthetic details asapplied to the title compound. Additional compounds can be preparedaccording to this method by varying the coupling reagents.

(R)-3-amino-5-bromo-4-((1-((tert-butyldimethylsilypoxy)propan-2-yl)amino)-N-(4-(chlorodifluoromethoxy)phenyl)benzamide(42a). A mixture of(R)-3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(1-hydroxypropan-2-yl)amino)benzamide(33a, 2 g, 4.30 mmol), imidazole (439.50 mg, 6.46 mmol), TBSCl (973.05mg, 6.46 mmol, 791.10 uL) and DMAP (52.58 mg, 430.40 umol) in DCM (30mL) was degassed and purged with N₂ three times, and then the mixturewas stirred at 15° C. for 2 hr under a N₂ atmosphere. TLC (petroleumether:ethyl acetate=3:1, R_(f)=0.5) showed a new spot was generated.LCMS showed a peak with desired MS was detected. The reaction mixturewas concentrated and H₂O (20 mL) was added. The aqueous phase wasextracted with ethyl acetate (30 mL×3). The combined organic layers werewashed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (petroleum ether:ethyl acetate=10:1˜5:1) to give42a as a yellow oil. ¹H NMR (400 MHz, CDCl₃-d) δ 7.69 (br s, 1H), 7.66(d, J=9.0 Hz, 2H), 7.37 (d, J=1.8 Hz, 1H), 7.25 (br d, J=8.8 Hz, 2H),7.14 (d, J=1.8 Hz, 1H), 4.31 (br s, 2H), 3.78-3.66 (m, 2H), 3.62-3.50(m, 2H), 1.15 (d, J=6.2 Hz, 3H), 0.94 (s, 9H), 0.11 (s, 6H).

(R)-7-bromo-1-(1-((tert-butyldimethylsilypoxy)propan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide(42b). A mixture of(R)-3-amino-5-bromo-4-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)amino)-N-(4-(chlorodifluoromethoxy)phenyl)benzamide(42a, 2.4 g, 4.15 mmol), di(imidazol-1-yl)methanethione (2.22 g, 12.44mmol), DIEA (1.07 g, 8.29 mmol, 1.44 mL) in THF (20 mL) was degassed andpurged with N₂ three times. The mixture was stirred at 60° C. for 16 hrunder a N₂ atmosphere. TLC (petroleum ether:ethyl acetate=2:1,R_(f)=0.54) indicated a new spot was generated. LCMS showed a peak withdesired MS was detected. The mixture was concentrated and H₂O (50 mL)was added. The aqueous phase was extracted with ethyl acetate (50 mL×3).The combined organic layers were washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude productwas purified by silica gel column chromatography (petroleum ether:ethylacetate=8:1˜2:1) to give 42b as a yellow solid. ¹H NMR (400 MHz,CDCl₃-d) δ 11.21 (s, 1H), 7.96 (s, 1H), 7.86 (d, J=1.1 Hz, 1H),7.75-7.67 (m, 3H), 7.28 (s, 1H), 7.26 (s, 1H), 6.11-5.97 (m, 1H), 4.99(t, J=9.6 Hz, 1H), 3.95 (dd, J=5.1, 10.4 Hz, 1H), 1.86 (d, J=7.1 Hz,3H), 0.68 (s, 9H), 0.00 (s, 3H),-0.12 (s, 3H).

(R)-7-bromo-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(methylthio)-1H-benzo[d]imidazole-5-carboxamide(42c). To a solution of(R)-7-bromo-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide(42b, 2.4 g, 3.86 mmol) in DMF (20 mL) was added MeI (822.82 mg, 5.80mmol, 360.89 uL) and K₂CO₃ (1.07 g, 7.73 mmol). The mixture was stirredat 15° C. for 2 hr. TLC (petroleum ether:ethyl acetate=2:1, R_(f)=0.72)indicated a new spot was generated. LCMS showed a peak with desired MSwas detected. The mixture was quenched with water (50 mL) and extractedwith ethyl acetate (50 mL×3), the combined organic layers were washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (petroleum ether:ethyl acetate=3:1˜2:1) to give42c as a yellow oil. ¹H NMR (400 MHz, CDCl₃-d) δ 8.03 (d, J=1.6 Hz, 1H),7.97 (d, J=1.6 Hz, 1H), 7.89 (s, 1H), 7.74-7.67 (m, 2H), 7.28 (s, 1H),7.25 (s, 1H), 6.21-6.05 (m, 1H), 4.28 (dd, J=9.2, 10.4 Hz, 1H), 3.89(dd, J=5.7, 10.6 Hz, 1H), 2.83 (s, 3H), 1.67 (d, J=7.3 Hz, 3H), 0.67 (s,9H), −0.04 (s, 3H), −0.18 (s, 3H)

(R)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(1-hydroxypropan-2-yl)-2-(methylthio)-1H-benzo[d]imidazole-5-carboxamide(42d). To a solution of(R)-7-bromo-1-(1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(methylthio)-1H-benzo[d]imidazole-5-carboxamide(42c, 1 g, 1.57 mmol) in THF (20 mL) was added TBAF (1M, 1.73 mL). Themixture was stirred at 15° C. for 3 hr. TLC (petroleum ether:ethylacetate=0:1, R_(f)=0.65) showed a new spot was generated. LCMS showed apeak with desired MS was detected. The mixture was quenched with AcONH₄(30 mL) and extracted with ethyl acetate (50 mL×3). The combined organiclayers were washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bysilica gel column chromatography (petroleum ether:ethyl acetate=3:1˜0:1)to give 42d as a yellow solid. ¹H NMR (400 MHz, CDCl₃-d) δ 8.63 (s, 1H),7.87 (d, J=9.0 Hz, 2H), 7.62 (d, J=1.7 Hz, 2H), 7.31 (d, J=8.8 Hz, 2H),6.14 (ddd, J=4.6, 7.4, 10.0 Hz, 1H), 4.59 (dd, J=10.0, 12.7 Hz, 1H),3.91 (dd, J=4.4, 12.8 Hz, 1H), 2.84 (s, 3H), 1.59 (d, J=7.3 Hz, 3H).

(R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide(42e) A solution of(R)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(1-hydroxypropan-2-yl)-2-(methylthio)-1H-benzo[d]imidazole-5-carboxamide(42d, 500 mg, 960.11 umol) in DMF (6 mL) was degassed and purged with O₂three times and the mixture cooled to 0° C. NaH (46.08 mg, 1.15 mmol,60% purity, 1.2 eq) was added. The mixture was stirred at 0˜15° C. for 6hr under O₂. TLC (petroleum ether:ethyl acetate=1:2, R_(f)=0.5) showed anew spot was generated. LCMS showed a peak with desired MS was detected.The mixture was quenched with NH₄Cl (50 mL) and extracted with ethylacetate (50 mL×3), the combined organic layers were washed with brine(20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by silica gel columnchromatography (petroleum ether:ethyl acetate=2:1-0:1) to give 42e as awhite solid. ¹H NMR (400 MHz, CDCl₃-d) δ 8.24 (s, 1H), 7.90 (dd, J=1.3,15.9 Hz, 2H), 7.74 (d, J=9.0 Hz, 2H), 7.25 (s, 1H), 5.29-5.19 (m, 1H),5.09-4.98 (m, 1H), 4.78 (dd, J=2.2, 8.6 Hz, 1H), 1.69 (d, J=6.4 Hz, 3H)

(R)-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-5-(pyridazin-3-yl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide(42). A mixture of(R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-methyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide(42e, 25 mg, 52.89 umol), tributyl(pyridazin-3-yl)stannane (39.05 mg,105.78 umol, 2 eq), palladium;tritert-butylphosphane (2.70 mg, 5.29umol, 0.1 eq) in dioxane (2 mL) was degassed and purged with N₂ threetimes, and then the mixture was stirred at 110° C. for 16 hr under N₂.TLC (ethyl acetate:methanol=10:1, R_(f)=0.31) showed a new spot wasgenerated. LCMS showed a peak with desired MS was detected. The reactionmixture was concentrated and H₂O (20 mL) was added. The aqueous phasewas extracted with ethyl acetate (30 mL×3). The combined organic layerswere washed with brine (10 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The crude product was purified by prep-TLC(ethyl acetate:methanol=10:1, R_(f)=0.31) to give a crude product, whichwas further purified by prep-HPLC (Column: Luna C18 100*30 5 u; mobilephase: [water (0.225%FA)-ACN]; B %: 20%-70%, 12 min.) to give 42 as alight yellow solid. MS mass calculated for [M+1]⁺ (C₂₂H₁₆ClF₂N₅O₃)requires m/z 472.1, LCMS found m/z 472.0; ¹H NMR (400 MHz, MeOD-d₄) 69.28 (dd, J=1.5, 4.9 Hz, 1H), 8.33 (dd, J=1.5, 8.6 Hz, 1H), 8.21-8.17(m, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.95 (dd, J=5.0, 8.6 Hz, 1H), 7.88-7.84(m, 2H), 7.31 (d, J=9.0 Hz, 2H), 5.39-5.26 (m, 2H), 4.83 (dd, J=2.8, 8.4Hz, 1H), 0.94 (d, J=6.4 Hz, 3H).

Example 43 General Procedure T(S)-N-(4-(chlorodifluoromethoxy)phenyl)-2-hydroxy-9-(pyrimidin-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide

This General Procedure T provides particular synthetic details asapplied to the title compound. Additional compounds can be preparedaccording to this method by varying the coupling reagents.

(S)-methyl3-amino-5-bromo-4-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)benzoate(43b). To a mixture of (S)-methyl3-amino-5-bromo-4-(3-hydroxypiperidin-1-yl)benzoate (synthesized in asimilar fashion to 1d; 43a, 970 mg, 2.95 mmol) and imidazole (501.52 mg,7.37 mmol) in DCM (20 mL) at 20° C. was added TBSCl (666.18 mg, 4.42mmol) and DMAP (36.00 mg, 0.295 mmol) in one portion under N₂. Themixture was stirred at 20° C. for 12 hours. TLC (petroleum ether:ethylacetate=3:1, R_(f)=0.7) indicated 43a was consumed completely and onenew spot formed. The mixture was washed with water (8 mL×3) and brine (8mL), dried over Na₂SO₄, filtered and concentrated to give 43b as ayellow oil, which was used in the next step without furtherpurification.

(S)-methyl9-bromo-2-((tert-butyldimethylsilyl)oxy)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(43c). To a solution of (S)-methyl3-amino-5-bromo-4-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)benzoate(43b, 1.18 g, 2.66 mmol) in 2,2,2-trifluoroethanol (10 mL) at 20° C.under N₂ was added chloroiridium;(1Z,5Z)-cycloocta-1,5-diene (268.11 mg,0.399 mmol) in one portion. The mixture was heated to 85° C. and stirredfor 72 hours. LCMS showed 43b was consumed completely and one main peakwith desired mass was detected. TLC (petroleum ether:ethyl acetate=1:1,R_(f)=0.4) indicated 43b was consumed completely and one new spotformed. The reaction mixture was concentrated under reduced pressure toremove solvent. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=20/1 to 2/1) to give 43c as a yellow oil.¹H NMR (400 MHz, CDCl₃-d) δ 8.30 (s, 1H), 8.08 (s, 1H), 4.69-4.57 (m,2H), 4.46 (br d, J=3.9 Hz, 1H), 4.15-4.06 (m, 1H), 3.95 (s, 3H),3.41-3.29 (m, 1H), 3.12-3.07 (m, 1H), 2.13-2.09 (m, 1H), 0.88 (s, 9H),0.15 (br d, J=6.4 Hz, 6H).

(S)-methyl9-bromo-2-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(43d). To a solution of (S)-methyl9-bromo-2-((tert-butyldimethylsilyl)oxy)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(43c, 550 mg, 1.25 mmol) in THF (10 mL) at 20° C. was added TBAF (1M,1.38 mL) in one portion. The mixture was stirred at 20° C. for 30 min.TLC (ethyl acetate:methanol=10:1) indicated 43c was consumed completelyand one new spot formed. The mixture was concentrated under reducedpressure. The residue was dissolved into EtOAc (20 mL), washed withwater (7 mL×3) and brine (5 mL), dried over Na₂SO₄, filtered andconcentrated to give 43d as a yellow oil, which was used in the nextstep without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (d,J=1.3 Hz, 1H), 7.90 (d, J=1.5 Hz, 1H), 5.34 (d, J=3.4 Hz, 1H), 4.57 (d,J=3.9 Hz, 2H), 4.37-4.28 (m, 1H), 3.87 (s, 3H), 3.18-2.96 (m, 2H),2.04-1.99 (m, 2H).

(S)-9-bromo-2-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylicacid (43e). To a solution of (S)-methyl9-bromo-2-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(43d, 320 mg, 0.984 mmol) in THF at 20° C. (5 mL) and H₂O (2 mL) wasadded LiOH.H₂O (61.95 mg, 1.48 mmol) in one portion. The mixture wasstirred at 20° C. for 16 hours. LCMS showed 43d was consumed completelyand one main peak with desired mass was detected. The reaction mixturewas concentrated under reduced pressure to remove solvent. The residuewas dissolved into H₂O (1 mL) and the pH was adjusted to 4-5 by HCl(1M). The mixture was filtered and the filter cake was washed with H₂O(0.5 mL) to give 43e as a white solid, which was used in the next stepwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 1H),7.88 (s, 1H), 5.41-5.28 (m, 1H), 4.56 (br s, 2H), 4.38-4.25 (m, 1H),3.16-2.91 (m, 2H), 1.99 (br s, 2H).

(S)-9-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(43f). To a mixture of(S)-9-bromo-2-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylicacid (43e, 280 mg, 899.94 umol) and HATU (376.40 mg, 989.93 umol) in DMF(3 mL) at 20° C. was added 4-(chlorodifluoromethoxy)aniline (1 h, 209.05mg, 1.08 mmol) and DIPEA (232.62 mg, 1.80 mmol) in one portion. Themixture was stirred at 20° C. for 12 hours. LCMS showed 43e was consumedcompletely and one main peak with desired mass was detected. TLC(methanol:dichloromethane=10:1, R_(f)=0.41) indicated 43e was consumedcompletely and one new spot formed. The mixture was poured into EtOAc(20 mL), washed with water (5 mL×4) and brine (5 mL), dried over Na₂SO₄,filtered and concentrated. The residue was purified by prep-TLC (SiO₂,ethyl acetate:methanol=10:1) to give 43f as a yellow solid. ¹H NMR (400MHz, CDCl₃-d) δ 10.47 (s, 1H), 8.25 (d, J=1.1 Hz, 1H), 7.99 (d, J=1.2Hz, 1H), 7.96-7.90 (m, 2H), 7.36 (d, J=8.9 Hz, 2H), 5.37 (d, J=3.4 Hz,1H), 4.58 (d, J=3.8 Hz, 2H), 4.38-4.30 (m, 1H), 3.22-2.96 (m, 2H),2.04-1.99 (m, 2H).

(S)-N-(4-(chlorodifluoromethoxy)phenyl)-2-hydroxy-9-(pyrimidin-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(43). To a mixture of(S)-9-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(43f, 30 mg, 0.062 mmol) and pyrimidin-5-ylboronic acid (15.28 mg, 0.123mmol) in dioxane (2 mL) and H₂O (0.2 mL) at 20° C. under N₂ was addedPd(dppf)Cl₂ (4.51 mg, 6.16 umol) and K₃PO₄ (39.25 mg, 184.92 umol) inone portion. The mixture was heated to 110° C. and stirred for 12 hours.LCMS showed 43f was consumed completely and one main peak with desiredmass was detected. TLC (ethyl acetate:methanol=10:1, R_(f)=0.4)indicated 43f was consumed completely and one new spot formed. Themixture was filtered through a Celite pad. The pad was washed with EtOAc(10 mL) and the filtrate was concentrated to give the crude product. Theresidue was purified by prep-TLC (SiO₂, ethyl acetate:methanol=10:1) togive 43 as a yellow solid. Mass calculated for [M+1]⁺ (C₂₃H₁₈ClF₂N₅O₃)requires m/z 486.1, LCMS found m/z 486.1; ¹H NMR (400 MHz, DMSO-d₆) δ10.44 (s, 1H), 9.34 (s, 1H), 9.06 (s, 2H), 8.37 (d, J=1.6 Hz, 1H), 7.94(d, J=9.2 Hz, 2H), 7.76 (d, J=1.5 Hz, 1H), 7.37 (d, J=9.0 Hz, 2H), 5.16(d, J=3.3 Hz, 1H), 4.12 (br d, J=2.1 Hz, 1H), 3.84 (dd, J=3.7, 11.7 Hz,1H), 3.45 (br dd, J=4.4, 11.7 Hz, 1H), 3.19-2.97 (m, 2H), 2.02-1.92 (m,2H).

Example 44 General Procedure U(S)-N-(4-(chlorodifluoromethoxy)phenyl)-3-hydroxy-6-(1H-pyrazol-5-yl)-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-8-carboxamide

This General Procedure U provides particular synthetic details asapplied to the title compound. Additional compounds can be preparedaccording to this method by varying the coupling reagents.

(S)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(2,3-dihydroxypropyl)amino)-5-nitrobenzamide(44b). To a mixture of3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluoro-5-nitrobenzamide(24c, 1.2 g, 2.73 mmol) and (S)-3-aminopropane-1,2-diol (44a, 261.16 mg,2.87 mmol, 221.32 uL) in EtOH (3 mL) was added TEA (552.49 mg, 5.46mmol, 759.96). The mixture was stirred at 25° C. for 12 hours. LCMSshowed the desired MS. The mixture was concentrated and poured intowater, filtered to give 44b as a red solid. ¹H NMR (400 MHz, MeOD-d₄) δ8.53 (d, J=2.1 Hz, 1H), 8.38 (d, J=2.2 Hz, 1H), 7.80 (d, J=9.0 Hz, 2H),7.28 (br d, J=8.9 Hz, 2H), 3.83-3.75 (m, 1H), 3.61-3.41 (m, 3H),3.26-3.22 (m, 1H).

3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-nitro-4-((((4S)-2-phenyl-1,3-dioxolan-4-yl)methyl)amino)benzamide(44d). To a mixture of(S)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((2,3-dihydroxypropyl)amino)-5-nitrobenzamide(44b, 1.2 g, 2.35 mmol) and TsOH (40.46 mg, 0.235 mmol) in DCM (10 mL)at 0° C. under N₂ was added dimethoxymethylbenzene (44c, 1.07 g, 7.05mmol, 1.06 mL). The mixture was stirred at 25° C. for 12 hours. TLC(petroleum ether:ethyl acetate=3:1, R_(f)=0.60) indicated 44b wasconsumed completely and two new spots formed. The mixture was extractedwith ethyl acetate (30 mL×3), the combined organic layers were washedwith brine (50 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, petroleum ether:ethyl acetate=100:1 to 3:1, R_(f)=0.60) to give44d as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1H), 10.43(s, 1H), 8.54 (d, J=2.1 Hz, 1H), 8.47 (d, J=2.1 Hz, 1H), 8.46 (d, J=2.1Hz, 1H), 8.42 (d, J=2.2 Hz, 1H), 7.89 (d, J=1.3 Hz, 2H), 7.86 (s, 2H),7.42-7.31 (m, 14H), 6.75 (t, J=5.7 Hz, 1H), 6.67 (t, J=5.7 Hz, 1H), 5.84(s, 1H), 5.72 (s, 1H), 4.51-4.42 (m, 2H), 4.18 (dd, J=6.6, 8.4 Hz, 1H),3.94 (dd, J=5.0, 8.5 Hz, 1H), 3.73 (dd, J=6.4, 8.5 Hz, 1H), 3.61-3.53(m, 1H), 3.49-3.42 (m, 2H).

3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((((4S)-2-phenyl-1,3-dioxolan-4-yl)methyl)amino)benzamide(44e). To a solution of3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-5-nitro-4-((((4S)-2-phenyl-1,3-dioxolan-4-yl)methyl)amino)benzamide(44d, 0.7 g, 1.17 mmol) in AcOH (10 mL) was added Fe (652.86 mg, 11.69mmol). The mixture was stirred at 35° C. for 0.5 hr. TLC indicated 44dwas consumed completely and one new spot formed. The mixture was pouredinto water and extracted with ethyl acetate (10 mL×2). The combinedorganic layers were washed with sat. NaHCO₃, washed with brine (50mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuoto give 44e as a yellow oil.

7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(((4S)-2-phenyl-1,3-dioxolan-4-yl)methyl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide(44f). A solution of3-amino-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((((4S)-2-phenyl-1,3-dioxolan-4-yl)methyl)amino)benzamide(44f, 0.9 g, 1.58 mmol), di(imidazol-1-yl)methanethione (845.96 mg, 4.75mmol) in THF (10 mL) was added DIEA (408.99 mg, 3.16 mmol, 551.20 uL)and the mixture was stirred at 60° C. for 12 hours. LCMS showed thedesired MS. The mixture was extracted with ethyl acetate (30mL×2), thecombined organic layers were washed with brine (50 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by prep-TLC (SiO₂, petroleum ether:ethyl acetate=1:1,R_(f)=0.30) to give 44f as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ13.55 (s, 1H), 10.53 (s, 1H), 8.05 (dd, J=1.5, 4.2 Hz, 1H), 7.92-7.85(m, 2H), 7.78 (d, J=1.2 Hz, 1H), 7.50-7.45 (m, 1H), 7.42-7.33 (m, 6H),6.11-5.69 (m, 1H), 5.17-4.69 (m, 3H), 4.35-4.27 (m, 1H), 4.08-3.98 (m,1H).

7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(methylthio)-1-(((4S)-2-phenyl-1,3-dioxolan-4-yl)methyl)-1H-benzo[d]imidazole-5-carboxamide(44g). To a solution of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(((4S)-2-phenyl-1,3-dioxolan-4-yl)methyl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide(44f, 0.72 g, 1.18 mmol) in DMF (10 mL) was added MeI (184.03 mg, 1.30mmol, 80.72 uL) and K₂CO₃ (325.80 mg, 2.36 mmol). The mixture wasstirred at 25° C. for 2 hours. LCMS showed the desired MS. The mixturewas extracted with ethyl acetate (20 mL×3). The combined organic layerswere washed with brine (50 mL×2), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=100:1 to 1:1) togive 44g as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H),8.29 (d, J=1.2 Hz, 1H), 8.00 (s, 1H), 7.97-7.90 (m, 2H), 7.52-7.47 (m,1H), 7.43-7.33 (m, 5H), 6.07-5.70 (m, 1H), 4.85-4.60 (m, 3H), 4.46-3.91(m, 2H), 2.79-2.71 (m, 3H).

(S)-1-(2-(benzyloxy)-3-hydroxypropyl)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(methylthio)-1H-benzo[d]imidazole-5-carboxamide(44h). To a solution of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(methylthio)-1-(((4S)-2-phenyl-1,3-dioxolan-4-yl)methyl)-1H-benzo[d]imidazole-5-carboxamide(44g, 0.06 g, 0.96 mmol), ZnBr₂ (64.87 mg, 0.288 mmol, 14.42 uL) in DCM(2 mL) at 0° C. was added BH₃-Me₂S (10 M, 11.52 uL, 1.2 eq). The mixturewas stirred at 25° C. for 12 hours. LCMS showed the desired MS. Themixture was quenched by sat. NaHCO₃ and extracted with DCM (2 mL×2). Thecombined organic layers were washed with brine (5 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by prep-TLC (SiO₂, petroleum ether:ethyl acetate=0:1,R_(f)=0.40) to give 44h as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.43 (s, 1H), 8.28 (d, J=1.2 Hz, 1H), 7.97-7.91 (m, 3H), 7.37 (d, J=8.8Hz, 2H), 7.09-7.04 (m, 3H), 6.89-6.85 (m, 2H), 5.00 (t, J=5.6 Hz, 1H),4.68-4.59 (m, 1H), 4.47 (d, J=12.2 Hz, 2H), 4.13 (d, J=12.2 Hz, 1H),3.89 (br dd, J=4.0, 9.5 Hz, 1H), 3.67 (t, J=4.9 Hz, 2H), 2.72 (s, 3H).

(S)-3-(benzyloxy)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-8-carboxamide(44i). To a mixture of(S)-1-(2-(benzyloxy)-3-hydroxypropyl)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(methylthio)-1H-benzo[d]imidazole-5-carboxamide(44h, 20 mg, 0.032 mmol) in THF (2 mL) at 0° C. under O₂ was added NaH(1.78 mg, 0.045 mmol, 60% purity). The mixture was stirred at 25° C. for12 hours. LCMS showed the desired MS. The mixture was quenched by H₂Oand extracted with ethyl acetate (2 mL×3). The combined organic layerswere washed with brine (5 mL×2), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by prep-TLC (SiO₂,petroleum ether:ethyl acetate=0:1, R_(f)=0.40) to give 44i as a whitesolid.

(S)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-hydroxy-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-8-carboxamide(44j). To a mixture of(S)-3-(benzyloxy)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-8-carboxamide(44i, 30 mg, 0.052 mmol) in DCM (2 mL) at −70° C. under N₂ was addedBCl₃ (1M, 259.16 uL). The mixture was stirred at −70° C. for 1 hour.LCMS showed the desired MS. The reaction was quenched with water and DCM(3 mL×2). The combined organic layers were washed with brine (5 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give44j as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 8.08(s, 1H), 7.95-7.86 (m, 3H), 7.36 (br d, J=8.8 Hz, 2H), 4.66 (br d,J=11.9 Hz, 1H), 4.58-4.49 (m, 2H), 4.46-4.36 (m, 2H).

(S)-N-(4-(chlorodifluoromethoxy)phenyl)-3-hydroxy-6-(1H-pyrazol-5-yl)-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-8-carboxamide(44). To a solution of(S)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-hydroxy-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-8-carboxamide(44j, 15 mg, 0.031 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (17.87 mg,0.092 mmol) in dioxane (2 mL), H₂O (0.2 mL) was added K₃PO₄ (19.55 mg,0.092 mmol) and Pd(dppf)Cl₂ (2.25 mg, 3.07 umol), (Boc)₂O (6.70 mg,0.031 umol, 7.05 uL). The mixture was stirred at 110° C. for 12 hours.TLC (ethyl acetate: methanol=10:1, R_(f)=0.24) indicated 44j wasconsumed completely and many new spots formed. The mixture was filteredand poured into water, extracted with ethyl acetate (5 mL×2). Thecombined organic layers were washed with brine (10 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by prep-TLC (SiO₂, ethyl acetate: methanol=10:1) to give 44 asa yellow solid. ¹H NMR (400 MHz, MeOD-d₄) δ 8.06 (s, 1H), 7.85-7.77 (m,4H), 7.28 (d, J=9.0 Hz, 2H), 6.64 (s, 1H), 4.57-4.44 (m, 2H), 4.28 (brs, 1H), 4.12 (br d, J=13.1 Hz, 1H), 3.73 (br s, 1H).

Example 45 General Procedure V(S)-N-(4-(chlorodifluoromethoxy)phenyl)-4-(hydroxymethyl)-6-(pyridazin-3-yl)-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-8-carboxamide

This General Procedure V provides particular synthetic details asapplied to the title compound. Additional compounds can be preparedaccording to this method by varying the coupling reagents.

(S)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(hydroxymethyl)-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-8-carboxamide(45b),(S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-(2-hydroxyethyl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide(45c). To a solution of(S)-7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-(1,4-dihydroxybutan-2-yl)-2-(methylthio)-1H-benzo[d]imidazole-5-carboxamide(synthesized in a similar fashion to 42d; 45a, 260 mg, 0.472 mmol) inTHF (5 mL) at 0° C. was added NaH (28.32 mg, 0.708 mmol, 60% purity).The mixture was stirred at 20° C. for 1 hr under O₂. LCMS showed 45a wasconsumed completely and desired MS was detected. TLC (ethylacetate:methanol=10:1, P₁: R_(f)=0.5, P₂: R_(f)=0.4) showed the reactionwas completed. The mixture was diluted with aq.NH₄Cl (10 mL) andextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by silicagel chromatography (petroleum ether/ethyl acetate=5/1, 0/1, ethylacetate:methanol=20/1) to give 45b as a white solid and 45c as a whitesolid. (45b)¹H NMR (400 MHz, MeOD-d₄) δ 7.92 (d, J=1.5 Hz, 1H),7.83-7.77 (m, 2H), 7.62 (d, J=1.8 Hz, 1H), 7.29 (d, J=9.0 Hz, 2H),6.13-5.99 (m, 1H), 4.22 (q, J=7.6 Hz, 1H), 4.18-4.06 (m, 2H), 3.99 (dt,J=5.1, 8.0 Hz, 1H), 2.75-2.58 (m, 1H), 2.41-2.23 (m, 1H). (45c) iH NMR(400 MHz, DMSO-d6) 6 10.40 (s, 1H), 8.06 (d, J=1.1 Hz, 1H), 7.98-7.85(m, 3H), 7.35 (br d, J=9.0 Hz, 2H), 5.30-5.22 (m, 1H), 5.15 (dd, J=2.3,8.7 Hz, 1H), 5.12-5.00 (m, 1H), 4.68 (t, J=4.8 Hz, 1H), 3.52 (td, J=5.8,11.4 Hz, 2H), 2.27-2.14 (m, 1H), 2.09-2.00 (m, 1H).

(S)-N-(4-(chlorodifluoromethoxy)phenyl)-4-(hydroxymethyl)-6-(pyridazin-3-yl)-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-8-carboxamide(45). To a solution of(S)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(hydroxymethyl)-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-8-carboxamide(45b, 40 mg, 0.08 mmol) and tributyl(pyridazin-3-yl)stannane (58.74 mg,0.159 mmol) in dioxane (4 mL) was added palladium;tritert-butylphosphane(4.07 mg, 7.96 umol). The mixture was stirred at 110° C. for 16 hr underN₂. LCMS showed 45b was consumed completely and desired MS was detected.The reaction mixture was diluted with H₂O (5 mL) and extracted withEtOAc (10 mL×2). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Themixture was further purification by pre-HPLC (FA, column: PhenomenexLuna C18 200*40 mm*10 um; mobile phase: [water(0.225%FA)-ACN];B %:40%-70%,12 min) to give 45 as a white solid. MS mass calculated for[M+1]⁺ (C₂₃H₁₈ClF₂N₅O₄) requires m/z 502.1, LCMS found m/z 502.1; ¹H NMR(400 MHz, MeOD-d₄) δ 9.35 (dd, J=1.5, 5.1 Hz, 1H), 8.17 (dd, J=1.4, 8.5Hz, 1H), 8.01 (dd, J=5.1, 8.4 Hz, 1H), 7.84-7.78 (m, 3H), 7.76 (d, J=1.8Hz, 1H), 7.29 (d, J=9.0 Hz, 2H), 4.16-3.99 (m, 3H), 3.91-3.82 (m, 1H),3.79-3.70 (m, 1H), 2.54-2.43 (m, 1H), 2.01 (br s, 1H)

Example 46(R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-9-(pyridazin-3-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide

Methyl9-bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(46b). To a mixture of methyl 3-amino-5-bromo-4-(piperidin-1-yl)benzoate(46a, 1.8 g, 5.75 mmol) in HCOOH (20 mL) was added H₂O₂ (5.86 g, 51.73mmol, 4.97 mL, 30% purity) under N₂. The mixture was stirred at 110° C.for 40 mins. LCMS showed the desired MS. The mixture was quenched withsat. Na₂S₂O₃, made basic with NaHCO₃ (pH=7) and extracted with ethylacetate (50 mL×3). The combined organic layers were washed with brine(100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by column chromatography (SiO₂,petroleum ether:ethyl acetate=100:1 to 0:1, R_(f)=0.20) to give 46b as abrown solid.

Methyl 4,9-dibromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate (46c). To a solution of methyl9-bromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(46b, 0.7 g, 2.26 mmol), AIBN (37.18 mg, 0.226 umol) in CCl₄ (20 mL) wasadded NBS (402.99 mg, 2.26 mmol). The mixture was stirred at 50° C. for12 hours. LCMS showed the desired MS. The mixture was quenched by H₂Oand extracted with DCM (30 mL×2). The combined organic layers werewashed with brine (50 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, petroleum ether:ethyl acetate=100:1 to 1:1, R_(f)=0.50) to give46c as a brown solid.

Methyl9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(46d). To a solution of methyl4,9-dibromo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(46c, 0.7 g, 1.80 mmol) in MeCN (5 mL) and H₂O (5 mL) was added Oxone(2.22 g, 3.61 mmol). The mixture was stirred at 50° C. for 12 hours.LCMS showed the desired MS. The mixture was concentrated, poured intowater and extracted with ethyl acetate (10 mL×2). The combined organiclayers were washed with brine (30 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=100:1 to 0:1) togive 46d as a white solid.

Methyl9-bromo-4-oxo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(46e). To a solution of methyl9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(46d, 0.3 g, 0.922 mmol) in DCM (5 mL) was added DMP (395.24 mg, 0.932mmol) at 0° C. The mixture was stirred at 25° C. for 10 mins. TLC(petroleum ether:ethyl acetate=0:1, R_(f)=0.50) indicated 46d wasconsumed completely and one new spot formed. The mixture was poured intowater and extracted with ethyl acetate (3 mL×2). The combined organiclayers were washed with brine (5 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by prep-TLC(SiO₂, petroleum ether:ethyl acetate=0:1, R_(f)=0.50) to give 46e as abrown solid.

(R)-methyl9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(46f). A solution of dichlororuthenium;1-isopropyl-4-methyl-benzene(18.00 mg, 29.40 umol),N-[(1R,2R)-2-amino-1,2-diphenyl-ethyl]-4-methyl-benzenesulfonamide(25.86 mg, 70.56 umol) in H₂O (10 mL) was stirred at 70° C. for 1.5hours. Sodium formate (199.93 mg, 2.94 mmol, 158.68 uL), methyl9-bromo-4-oxo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(46e, 0.19 g, 0.588 mmol) in THF (5 mL) was added and the mixture wasstirred at 40° C. for 0.5 hours. LCMS showed the desired MS. The mxiturewas filtered, poured into water and extracted with ethyl acetate (10mL×2). The combined organic layers were washed with brine (30 mL×1),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by prep-TLC (SiO₂, petroleum ether:ethylacetate=0:1, R_(f)=0.20) to give 46f as a yellow solid.

(R)-9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylicacid (46g). To a solution of (R)-methyl9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(46f, 0.06 g, 0.185 mmol) in MeOH (0.5 mL), THF (0.5 mL) and H₂O (0.1mL) was added LiOH.H₂O (15.49 mg, 0.369 mmol). The mixture was stirredat 50° C. for 0.5 hours. LCMS showed the desired MS. TLC (ethylacetate:methanol=10:1, R_(f)=0.05) and indicated 46f was consumedcompletely. The mixture was concentrated and poured into aq. HCl (1M) toadjust the pH=5-6. The precipitate was filtered and dried to give 46g asa white solid.

(R)-9-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(46h). To a solution of(R)-9-bromo-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylicacid (46g, 0.06 g, 0.193 mmol), 4-[chloro(difluoro)methoxy]aniline (1h,41.06 mg, 0.212 mmol) in DMF (2 mL) was added HATU (87.99 mg, 0.23 mmol)and DIEA (74.77 mg, 0.579 mmol, 100.77 uL). The mixture was stirred at25° C. for 12 hours. LCMS showed the desired MS. The mixture wasextracted with ethyl acetate (3 mL×3). The combined organic layers werewashed with brine (5 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by prep-TLC (SiO₂, ethylacetate:methanol=10:1, R_(f)=0.40) to give 46h as a yellow oil.

(R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-9-(pyridazin-3-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(46). To a solution of(R)-9-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(46h, 0.05 g, 0.103 mmol), tributyl(pyridazin-3-yl)stannane (75.84 mg,0.205 mmol) in dioxane (2 mL) was added palladium;tritert-butylphosphane(5.25 mg, 10.27 umol). The mixture was stirred at 120° C. for 12 hours.LCMS showed the desired MS. The mixture was filtered and poured intowater and extracted with ethyl acetate (5mL×2). The combined organiclayers were washed with brine (10 mL×1), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified byprep-HPLC (FA, column: Phenomenex Luna C18 200*40 mm*10 um; mobilephase: [water (0.225%FA)-ACN]; B %: 20%-50%, 12 min) to give 46 as ayellow solid. ¹H NMR (400 MHz, MeOD-d₄) δ 9.31 (dd, J=1.4, 5.0 Hz, 1H),8.45 (d, J=1.3 Hz, 1H), 8.13 (dd, J=1.5, 8.4 Hz, 1H), 7.96 (d, J=1.5 Hz,1H), 7.93 (dd, J=5.1, 8.4 Hz, 1H), 7.85 (d, J=9.0 Hz, 2H), 7.30 (d,J=9.3 Hz, 2H), 5.06-5.00 (m, 1H), 3.82-3.72 (m, 2H), 2.20 (br d, J=11.5Hz, 2H), 2.07-2.00 (m, 1H), 1.98-1.86 (m, 1H).

Example 47(2S,3S)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(hydroxymethyl)-3-methyl-5-(1H-pyrazol-5-yl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide

(3S,4S)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-hydroxy-4-methyl-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-8-carboxamide(47b). NaHMDS (1M, 21.79 uL) was added to a solution of7-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-((2S,3S)-3,4-dihydroxybutan-2-yl)-2-(methylthio)-1H-benzo[d]imidazole-5-carboxamide (synthesized in a similar fashion to 45a;47a, 10 mg, 0.018 mmol) in THF (1 mL) at 0° C. The solution was stirredat 20° C. for 40 min under O₂. TLC showed 47a disappeared and four newmain spots appeared. LCMS detected the desired MS and showed that thereaction was complete. NH₄Cl (10 mL) was added to the mixture dropwiseand the reaction was extracted with ethyl acetate (5 mL×3). The combinedorganic layers were washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by prep-TLC(petroleum ether:ethyl acetate=0:1) to give 47b as a white solid. ¹H NMR(400 MHz, MeOD-d₄) δ 8.01 (d, J=1.3 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H),7.85-7.78 (m, 2H), 7.29 (br d, J=9.0 Hz, 2H), 5.51 (dt, J=5.2, 6.8 Hz,1H), 5.23-5.14 (m, 1H), 4.14-4.00 (m, 2H), 1.53 (d, J=6.6 Hz, 3H).

(2S,3S)-N-(4-(chlorodifluoromethoxy)phenyl)-2-(hydroxymethyl)-3-methyl-5-(1H-pyrazol-5-yl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]oxazole-7-carboxamide(47). To a solution of(3S,4S)-6-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-3-hydroxy-4-methyl-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine-8-carboxamide(47c, 30 mg, 0.06 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (34.74 mg,0.179 mmol) in dioxane (2 mL) at 20° C. and H₂O (0.2 mL) was addedPd(dppf)Cl₂ (4.37 mg, 5.97 umol), Boc₂O (6.51 mg, 0.03 mmol, 6.86 uL)and K₃PO₄ (38.00 mg, 0.179 mmol). The reaction was stirred at 120° C.for 16 hr. LCMS detected the desired MS and showed that the reaction wascomplete. The mixture was concentrated to remove the solvent. Theresidue was purified by prep-TLC (ethyl acetate:methanol=10:1) to give47 as a white solid. MS mass calculated for [M+1]⁺ (C₂₂H₁₈ClF₂N₅O₄)requires m/z 490.1, LCMS found m/z 490.1; ¹H NMR (400 MHz, MeOD-d₄) δ8.02 (s, 2H), 7.87-7.79 (m, 3H), 7.30 (d, J=9.0 Hz, 2H), 6.81 (s, 1H),5.52-5.44 (m, 1H), 5.37 (br t, J=6.6 Hz, 1H), 4.08-3.91 (m, 2H), 0.93(br d, J=6.4 Hz, 3H).

Example 48(S)-N-(4-(chlorodifluoromethoxy)phenyl)-2-hydroxy-2-methyl-9-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide

(S)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxy-3-methylpiperidin-1-yl)-5-nitrobenzamide(48b). To a solution of3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluoro-5-nitrobenzamide(24c, 500 mg, 1.14 mmol) and (3S)-3-methylpiperidin-3-ol hydrochloride(48a, 206.98 mg, 1.36 mmol) in EtOH (6 mL) was added TEA (345.30 mg,3.41 mmol, 474.97 uL). The mixture was stirred at 15° C. for 16 hr. LCMSshowed the desired ms was detected. TLC (petroleum ether:ethylacetate=3:1, R_(f)=0.4) showed a new spot was generated. The reactionmixture was concentrated under reduced pressure to remove solvent. Theresidue was purified by column chromatography (SiO₂, petroleumether/ethyl acetate=60/1 to 1/1) to give 548b as a yellow solid. ¹H NMR(400 MHz, CDCl₃-d) δ 8.33 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.69 (d,J=9.0 Hz, 2H), 7.30 (s, 2H), 3.38 (br s, 1H), 3.28-3.00 (m, 1H), 2.93(br d, J=11.2 Hz, 1H), 2.61 (br s, 1H), 2.20 (br s, 1H), 1.89-1.63 (m,2H), 1.56 (s, 3H), 1.53-1.39 (m, 1H).

(S)-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxy-3-methylpiperidin-1-yl)-3-nitro-5-(1H-pyrazol-5-yl)benzamide(48c). A mixture of(S)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxy-3-methylpiperidin-1-yl)-5-nitrobenzamide(48b, 100 mg, 0.187 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (108.86 mg,0.561 mmol), K₃PO₄ (119.09 mg, 0.561 mmol), (Boc)₂O (20.41 mg, 0.094mmol, 21.48 uL) and Pd(dppf)Cl₂ (27.37 mg, 0.037 mmol) in dioxane (1 mL)and H₂O (0.1 mL) was degassed and purged with N₂ 3 times The mixture wasstirred at 110° C. for 16 hr under a N₂ atmosphere. LCMS showed thedeisred ms were detected. TLC (petroleum ether:ethyl acetate=1:1,R_(f)=0.45) showed a major spot was generated. The reaction mixture wasconcentrated under reduced pressure to remove solvent. The residue waspurified by prep-TLC (SiO₂, petroleum ether:ethyl acetate=1:1,R_(f)=0.45) to give 48c as a yellow solid. ¹H NMR (400 MHz, CDCl₃-d) δ8.09 (d, J=2.0 Hz, 1H), 8.05 (d, J=2.2 Hz, 1H), 7.95 (br s, 1H),7.73-7.68 (m, 3H), 7.29 (s, 1H), 6.61 (s, 1H), 3.02 (br s, 2H), 2.85 (d,J=11.5 Hz, 1H), 2.70 (br d, J=10.8 Hz, 1H), 1.75 (br d, J=15.0 Hz, 2H),1.46 (dt, J=4.6, 13.5 Hz, 2H), 1.34 (br s, 1H), 1.25 (s, 3H).

(S)-N-(4-(chlorodifluoromethoxy)phenyl)-2-hydroxy-2-methyl-9-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(48). To a solution of(S)-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxy-3-methylpiperidin-1-yl)-3-nitro-5-(1H-pyrazol-5-yl)benzamide(48c, 20 mg, 0.038 mol) in AcOH (1 mL) was added Fe (21.40 mg, 0.383mmol). The mixture was stirred at 35° C. for 1 hr. LCMS showed desiredms was detected. The reaction mixture was quenched by addition of EtOAc(15 mL). To the mixture was added NaHCO₃ (50 mL) and the mixture wasextracted with EtOAc (10 mL×3). The combined organic layers were washedwith brine (15mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified byprep-HPLC (neutral condition; column: Waters Xbridge BEH C18 100*25 mm*5um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 30%-45%, 10 min) togive 48 as a white solid. Mass calculated for [M+1]⁺ (C₂₃H₂₀ClF₂N₅O₃)requires m/z 488.1, LCMS found m/z 488.1. ¹H NMR (400 MHz, MeOD-d₄) δ8.25 (br s, 1H), 7.92-7.77 (m, 3H), 7.29 (br d, J=8.9 Hz, 2H), 6.63 (brs, 1H), 3.91-3.65 (m, 2H), 3.28-3.21 (m, 1H), 3.20-3.05 (m, 1H),2.14-1.94 (m, 2H), 1.30 (s, 3H).

Example 49 General Procedure W(1R,4R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-1-methyl-9-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide

This General Procedure W provides particular synthetic details asapplied to the title compound. Additional compounds can be preparedaccording to this method by varying the amines and coupling reagents.

(R)-methyl 3-bromo-4-(2-methylpiperidin-1-yl)-5-nitrobenzoate (49b). Toa solution of methyl 3-bromo-4-fluoro-5-nitrobenzoate (1a, 1000 mg, 3.60mmol) in DIPEA (4.65 g, 35.97 mmol, 6.26 mL) and was added(2R)-2-methylpiperidine (49a, 713.40 mg, 7.19 mmol). The mixture wasstirred at 40° C. for 16 hr. LCMS showed desired ms was detected. TLC(petroleum ether:ethyl acetate=5:1,R_(f)=0.60) showed a new major spotwas generated. The reaction mixture was concentrated under reducedpressure to remove solvent. The residue was diluted with H₂O (5 mL) andextracted with EtOAc (5 mL×3). The combined organic layers were washedwith brine (5 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, petroleum ether/ethyl acetate=50/1 to 10/1) togive 49b as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.38 (br s, 1H),8.15 (br s, 1H), 3.97-3.92 (m, 1H), 3.95 (s, 2H), 3.11 (br d, J=11.5 Hz,2H), 1.76 (br d, J=13.1 Hz, 2H), 1.63 (br s, 1H), 1.53-1.41 (m, 1H),1.39-1.23 (m, 1H), 0.83 (br s, 3H).

(R)-methyl 3-amino-5-bromo-4-(2-methylpiperidin-1-yl)benzoate (49c). Toa solution of methyl(R)-methyl3-bromo-4-(2-methylpiperidin-1-yl)-5-nitrobenzoate (49b, 0.78g, 2.18 mmol) in AcOH (5 mL) was added Fe (1.22 g, 21.84 mmol). Themixture was stirred at 35° C. for 1 hr. LCMS showed desired ms wasdetected. The reaction mixture was filtered and concentrated underreduced pressure to give a residue. The mixture was dissovled with EtOAcand washed with NaHCO₃. The organic layer was concentrated under reducedpressure to give 49c as brown oil, which was used in the next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃-d) δ =7.49 (d,J=1.8 Hz, 1H), 7.32 (d, J=1.8 Hz, 1H), 4.56 (br s, 2H), 3.88 (s, 3H),3.74-3.61 (m, 1H), 3.38 (dt, J=2.4, 11.8 Hz, 1H), 2.74 (br d, J=11.7 Hz,1H), 1.90-1.67 (m, 3H), 1.66-1.38 (m, 3H), 1.35-1.19 (m, 2H), 0.81 (d,J=6.4 Hz, 3H).

(R)-methyl9-bromo-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(49d). To a solution of methyl (R)-methyl3-amino-5-bromo-4-(2-methylpiperidin-1-yl) benzoate (49c, 300 mg, 0.917mmol) in 2,2,2-trifluoroethanol (2 mL) was added chloroiridium;(1Z,5Z)-cycloocta-1,5-diene (92.38 mg, 0.138 mmol). The mixture wasstirred at 80° C. for 4 hr under an O₂ atmosphere. LCMS showed desiredms was detected. The reaction mixture was filtered and concentratedunder reduced pressure to give a residue. The residue was purified byprep-HPLC (neutral condition; column: Waters Xbridge Prep OBD C18 150*40mm*10 um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 30%-65%, 8min)to give 49d as a brown solid. ¹H NMR (400 MHz, CDCl₃-d) δ 8.29 (d, J=1.3Hz, 1H), 8.10 (d, J=1.3 Hz, 1H), 5.45 (br t, J=6.2 Hz, 1H), 3.95 (s,3H), 3.27 (br dd, J=5.0, 17.3 Hz, 1H), 3.01 (ddd, J=6.4, 11.2, 17.9 Hz,1H), 2.28-2.06 (m, 3H), 2.03 (s, 1H), 1.52 (d, J=6.6 Hz, 3H).

(1R)-methyl4,9-dibromo-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(49e). To a solution of (R)-methyl9-bromo-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(49d, 30 mg, 0.093 mmol) in CCl₄ (1 mL) was added NBS (16.52 mg, 0.093mmol) and AIBN (1.52 mg, 0.0093 mmol). The mixture was stirred at 50° C.for 12 hr. TLC (petroleum ether:ethyl acetate=0:1,R_(f)=0.7) showed anew spot with low polarity was formed. AIBN (5.33 mg, 0.032 mmol) andNBS (8.26 mg, 0.046 mmol) were added. The mixture was stirred at 50° C.for 12 hr. LCMS showed desired ms was detected. TLC (ethylacetate:petroleum ether=2:1, R_(f)=0.58) showed a new spot was formed.The reaction mixture was concentrated under reduced pressure to removesolvent. The residue was purified by prep-TLC (SiO₂, ethylacetate:petroleum ether=2:1, R_(f)=0.58) to give 49e as a white solid.¹H NMR (400 MHz, MeOD-d₄) δ 8.27 (d, J=1.3 Hz, 1H), 8.15 (d, J=1.3 Hz,1H), 5.76 (br s, 1H), 5.66-5.54 (m, 1H), 3.95 (s, 3H), 2.89-2.68 (m,2H), 2.37 (br d, J=15.4 Hz, 1H), 2.07 (br d, J=13.8 Hz, 1H), 1.66 (d,J=6.5 Hz, 1H), 1.50 (d, J=6.6 Hz, 3H).

(1R,4R)-methyl9-bromo-4-hydroxy-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(49f). (1R,4S)-methyl9-bromo-4-hydroxy-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(49g). To a solution of (1R)-methyl4,9-dibromo-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(49e, 40 mg, 0.099 mmol) in MeCN (2 mL) and H₂O (2 mL) was added Oxone(183.48 mg, 0.298 mmol). The mixture was stirred at 50° C. for 16 hr.LCMS showed desired ms was detectd. TLC (petroleum ether:ethylacetate=1:2 R_(f)=0.40) showed a new spot was formed. The reactionmixture was concentrated under reduced pressure to remove solvent. Theresidue was purified by prep-HPLC (FA condition; column: Phenomenex LunaC18 100*30 mm*5 um; mobile phase: [water (0.2%FA)-ACN];B %:15%-45%,10min) to give 49f as a white solid and 49g as a white solid.(49f) ¹H NMR (400 MHz, MeOD-d₄) δ 8.29 (d, J=1.3 Hz, 1H), 8.12 (d, J=1.3Hz, 1H), 5.54-5.43 (m, 1H), 5.01 (br s, 1H), 4.61 (br s, 1H), 3.94 (s,3H), 2.72-2.58 (m, 1H), 2.35 (tt, J=3.5, 14.4 Hz, 1H), 2.07 (br dd,J=2.6, 14.6 Hz, 1H), 1.92 (br d, J=14.6 Hz, 1H), 1.50 (d, J=6.4 Hz, 3H).(49g)¹1-INMR (400 MHz, MeOD-d4) 6 8.28 (s, 1H), 8.09 (s, 1H), 5.48-5.37(m, 1H), 4.93 (br s, 2H), 3.93 (s, 3H), 2.44-2.23 (m, 2H), 2.19-2.03 (m,2H), 1.55 (d, J=6.6 Hz, 3H).

(1R,4R)-9-bromo-4-hydroxy-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylicacid (49h). To a solution of (1R,4R)-methyl9-bromo-4-hydroxy-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(49f, 15 mg, 0.044 mmol) in MeOH (1 mL), THF (1 mL) and H₂O (1 mL) wasadded LiOH.H₂O (2.78 mg, 0.066 mmol). The mixture was stirred at 15° C.for 16 hr. TLC (petroleum ether:ethyl acetate=0:1) showed 49f remainedand a new spot was formed. LiOH.H₂O (927.89 ug, 0.022 mmol) was added tothe reaction mixture. The mixture was stirred at 15° C. for 16 hr. LCMSshowed desired ms were detected. The mixture was adjusted to pH=4 withaqueous HCl (1M) and concentrated to give 49h as a white solid, whichwas used in the next step without further purification. ¹H NMR (400 MHz,MeOD-d₄) δ 8.40 (d, J=1.1 Hz, 2H), 5.67 (br t, J=4.9 Hz, 1H), 5.20 (brd, J=3.2 Hz, 1H), 2.71-2.40 (m, 2H), 2.18-1.99 (m, 2H), 1.67 (d, J=6.6Hz, 3H).

(1R,4R)-9-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(49i). To a solution of(1R,4R)-9-bromo-4-hydroxy-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylic acid (49h, 10 mg, 0.031 mmol),4-[chloro(difluoro)methoxy]aniline (1h, 7.14 mg, 0.037 mmol) in DMF (1mL) was added HATU (14.03 mg, 0.037 mmol) and DIEA (11.92 mg, 0.092mmol, 16.07 uL). The mixture was stirred at 15° C. for 5 hr. LCMS showeddesired ms was detected. TLC (ethyl acetate:methanol=10:1, R_(f)=0.40)showed a new spot was formed. The reaction mixture was concentratedunder reduced pressure to remove solvent. The residue was diluted withH₂O (10 mL) and extracted with EtAOc (10 mL×3). The combined organiclayers were washed with brine, dried over Ns₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-TLC (SiO₂, ethyl acetate:methanol=10:1) to give 49i asa white solid. ¹H NMR (400 MHz, CDCl₃-d) δ 8.09 (d, J=1.3 Hz, 1H), 8.00(d, J=1.3 Hz, 1H), 7.71 (d, J=8.9 Hz, 2H), 7.25 (s, 1H), 5.46 (br t,J=5.8 Hz, 1H), 5.18 (br s, 1H), 2.76-2.60 (m, 1H), 2.39-2.17 (m, 2H),1.96-1.86 (m, 1H), 1.53 (d, J=6.6 Hz, 3H).

(1R,4R)-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-1-methyl-9-(1H-pyrazol-5-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(49). A mixture of(1R,4R)-9-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxamide(48i, 8 mg, 0.016 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.30 mg,0.048 mmol), K₃PO₄ (10.17 mg, 0.048 mmol), Pd(dppf)Cl₂ (1.17 mg, 1.60umol) in dioxane (2 mL) and H₂O (0.2 mL) was degassed and purged with N₂3 times. The mixture was stirred at 120° C. for 16 hr under a N₂atmosphere. LCMS showed desired ms was detected. The reaction mixturewas concentrated under reduced pressure to remove solvent. The residuewas purified by prep-HPLC (neutral condition; column: Waters Xbridge BEHC18 100*30 mm*10 um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %:35%-55%, 10 min) to give 49 as a white solid. Mass calculated for [M+1]⁺(C₂₃H₂₀ClF₂N₅O₃) requires m/z 488.1, LCMS found m/z 488.1. ¹H NMR (400MHz, MeOD-d₄) δ 8.34 (br s, 1H), 7.94 (s, 1H), 7.85 (d, J=8.9 Hz, 3H),7.30 (d, J=8.8 Hz, 2H), 6.69 (br s, 1H), 5.14-4.94 (m, 2H), 2.75-2.55(m, 1H), 2.25 (br t, J=14.2 Hz, 1H), 2.04 (br d, J=11.9 Hz, 1H), 1.73(br d, J=13.8 Hz, 1H), 0.88 (br d, J=6.2 Hz, 3H).

The compounds in the table below (Table 1) were made and can be madesimilarly following the procedures described above.

TABLE 1 Gen- eral Exam- LCMS Proce- ple Structure m/z ¹H NMR dure 50

458.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 9.34 (s, 1H), 9.10 (s,2H), 8.65 (s, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.14 (s, 1H), 7.98- 7.90(m, 2H), 7.77 (d, J = 1.5 Hz, 1H), 7.36 (d, J = 9.0 Hz, 2H), 4.03 (quin,J = 6.7 Hz, 2H), 1.32 (s, 3H), 1.30 (s, 3H). A 51

456.2 ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 9.31 (s, 1H), 9.14 (s,2H), 8.52-8.44 (m, 2H), 7.95 (d, J = 9.2 Hz, 2H), 7.88 (d, J = 1.6 Hz,1H), 7.38 (d, J = 9.0 Hz, 2H), 3.29 (dt, J = 3.7, 7.2 Hz, 1H), 0.84-0.75(m, 2H), 0.49-0.41 (m, 2H). A 52

470.1 ¹H NMR (400 MHz, CDCl₃) δ 9.38 (s, 1 H) 8.89 (br s, 2 H) 8.43 (brs, 2 H) 8.22 (br s, 1 H) 7.67-7.88 (m, 3 H) 7.29 (br s, 1 H) 4.38 (br s,1 H) 2.16-2.37 (m, 2 H) 1.99 (br d, J = 7.0 Hz, 2 H) 1.82 (br d, J = 9.9Hz, 1 H) 1.63-1.72 (m, 1 H). A 53

486.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.35 (s, 1H), 9.07 (s, 2H), 8.88 (s,1H), 8.50 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.90-7.80 (m,2H), 7.31 (d, J = 9.0 Hz, 2H), 4.71-4.62 (m, 1H), 4.24-4.08 (m, 2H),3.86-3.76 (m, 1H), 3.67 (dd, J = 4.8, 10.6 Hz, 1H), 2.28-2.16 (m, 2H). A54

484.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.33 (s, 1H), 9.09 (s,2H), 8.61 (s, 1H), 8.51 (d, J = 1.5 Hz, 1H), 7.93 (d, J = 8.1 Hz, 2H),7.80 (d, J = 1.3 Hz, 1H), 7.36 (d, J = 8.8 Hz, 2H), 4.22 (quin, J = 6.4Hz, 1H), 1.86-1.64 (m, 6H), 1.64-1.37 (m, 2H). A 55

500.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.39 (s, 1H), 9.13 (s,2H), 8.78 (s, 1H), 8.54 (d, J = 1.5 Hz, 1H), 7.94 (d, J = 9.3 Hz, 2H),7.85 (d, J = 1.5 Hz, 1H), 7.37 (br d, J = 9.0 Hz, 2H), 3.87 (br dd, J =3.7, 11.2 Hz, 2H), 3.90- 3.84 (m, 1H), 2.81 (br t, J = A 11.4 Hz, 2H),2.06-1.93 (m, 2H), 1.80 (br d, J = 14.1 Hz, 2H). 56

500.1 ¹H NMR (400 MHz, CDCl₃-d) δ 9.37 (s, 1H), 8.86 (s, 2H), 8.45 (brs, 2H), 8.19 (s, 1H), 7.71-7.86 (m, 3H), 7.29 (br s, 1H), 7.27 (s, 1H),4.51-4.64 (m, 1H), 3.94-4.07 (m, 1H), 3.16 (s, 3H), 2.44 (dt, J = 13.18,6.53 Hz, 2H), 2.04-2.20 (m, 2H). A 57

500.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1 H) 9.35 (s, 1 H) 9.06 (s,2 H) 8.63 (s, 1H) 8.51 (d, J = 1.8 Hz, 1 H) 7.94 (d, J = 9.3 Hz, 2 H)7.81 (d, J = 1.5 Hz, 1 H) 7.36 (d, J = 9.0 Hz, 2 H) 4.85 (s, 1H) 4.61(t, J = 7.7 Hz, 1 H) 2.21-2.36 (m, 2 H) 1.77-1.88 (m, 2 H) 1.15 (s, 3H). A 58

476.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.33 (s, 1H), 9.04 (s, 2H), 8.64 (s,1H), 8.49 (d, J = 1.6 Hz, 1H), 7.91-7.80 (m, 3H), 7.31 (d, J = 8.9 Hz,2H), 4.63 (d, J = 5.3 Hz, 1H), 4.51 (d, J = 5.1 Hz, 1H), 4.45-4.30 (m,1H), 1.51 (d, J = 6.2 Hz, 3H). A 59

474.1 ¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H), 9.07 (s, 2H), 8.95 (s,1H), 8.53 (d, J = 1.3 Hz, 1H), 7.93 (d, J = 9.0 Hz, 2H), 7.86 (d, J =1.3 Hz, 1H), 7.37 (d, J = 9.0 Hz, 2H), 4.08-4.01 (m, 1H), 3.60- 3.47 (m,2H), 1.35 (d, J = 6.8 Hz, 3H). A 60

474.0 ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1H), 9.34 (s, 1H), 9.06 (s,2H), 8.67 (s, 1H), 8.52 (d, J = 1.3 Hz, 1H), 7.94 (d, J = 9.0 Hz, 2H),7.78 (d, J = 1.1 Hz, 1H), 7.37 (d, J = 9.0 Hz, 2H), 4.07-3.91 (m, 1H),3.61-3.51 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H). A 61

488.1 ¹H NMR (400 MHz, DMSO-d₆) 10.46 (s, 1H), 9.35 (s, 1H), 9.05 (s,2H), 8.75 (s, 1H), 8.51 (d, J = 1.5 Hz, 1H), 7.93 (d, J = 9.0 Hz, 2H),7.81 (d, J = 1.5 Hz, 1H), 7.36 (d, J = 9.0 Hz, 2H), 4.89-4.61 (m, 1H),4.04 (quin, J = 8.0 Hz, 1H), 2.59 (ddd, J = 3.3, 9.2, A 15.3 Hz, 2H),2.40-2.31 (m, 2H). 62

488.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.37 (s, 1H), 9.07 (s,2H), 8.80 (s, 1H), 8.53 (d, J = 1.1 Hz, 1H), 7.94 (d, J = 9.0 Hz, 2H),7.86 (s, 1H), 7.37 (d, J = 8.8 Hz, 2H), 5.34- 5.10 (m, 1H), 4.74 (quin,J = 7.2 Hz, 1H), 2.87-2.71 (m, 2H), 2.23-2.07 (m, 2H). A 63

470.0 ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (br s, 1H), 9.36 (s, 1H), 9.13(s, 2H), 8.53 (d, J = 1.5 Hz, 1H), 8.51 (s, 1H), 7.91-7.97 (m, 2H), 7.83(d, J = 1.5 Hz, 1H), 7.37 (d, J = 9.0 Hz, 2H), 3.75 (d, J = 7.1 Hz, 2H),0.63-0.74 (m, 1H), 0.30-0.39 (m, 2H), 0.12- 0.22 (m, 2H). A 64

488.2 ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H), 9.35 (s, 1H), 9.08 (brs, 2H), 8.85 (s, 1H), 8.53 (d, 1.3 Hz, 1H), 7.93 (d, J = 9.0 Hz, 2H),7.83 (d, J = 1.5 Hz, 1H), 7.37 (br d, J = 8.9 Hz, 2H), 4.19-4.07 (m,1H), 3.59-3.40 (m, 2H), 3.06 (s, 3H), 1.38 (d, J = 6.8 Hz, 3H). A 65

488.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.42 (s, 1H), 9.14 (br s, 1H), 9.13(s, 2H), 8.59 (d, J = 1.5 Hz, 1H), 8.02 (d, J = 1.5 Hz, 1H). 7.93 (d, J= 9.0 Hz, 2H), 7.39 (d, J = 8.9 Hz, 2H), 4.45-4.36 (m, 1H), 3.65- 3.61(m, 2H), 3.41-3.40 (m, 1H), 3.40 (s, 2H), 1.57 (d, J = 6.8 Hz, 3H). A 66

502.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 9.33 (s, 1H), 9.04 (s,2H), 8.53 (s, 1H), 8.50 (d, J = 1.5 Hz, 1H), 7.92 (d, J = 9.0 Hz, 2H),7.75 (d, J = 1.5 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 4.84 (s, 1H), 3.73(q, J = 7.0 Hz, 1H), 1.45 (d, J = 7.1 Hz, 3H), 0.84 (s, 3H), 0.55 (s,3H). A 67

486.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1 H) 9.33 (s, 1 H) 9.00 (brs, 2 H) 8.63 (s, 1H) 8.50 (d, J = 1.8 Hz, 1 H) 7.88-8.02 (m, 2 H) 7.76(d, J = 1.5 Hz, 1 H) 7.36 (d, J = 9.0 Hz, 2 H) 5.23 (d, J = 5.1 Hz, 1 H)4.24-4.45 (m, 1 H) 3.69 (br s, 1 H) 2.68-2.79 (m, 1 H) 2.20 (ddd, J =11.5, 5.5, 3.1 A Hz, 1 H) 1.95 (br dd, J = 12.1, 6.4 Hz, 1 H) 1.69- 1.82(m, 1 H). 68

488.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.30 (s, 1H), 8.99 (s, 2H), 8.69 (s,1H), 8.49 (s, 1H), 7.91 (s, 1H), 7.84 (d, J = 9.0 Hz, 2H), 7.30 (br d, J= 8.8 Hz, 2H), 3.99 (s, 2H), 0.89 (s, 6H). A 69

476.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1 H) 9.35 (s, 1 H) 9.06 (brs, 2 H) 8.69 (s, 1 H) 8.54 (d, J = 1.8 Hz, 1 H) 7.94 (d, J = 9.0 Hz, 2H) 7.79 (d, J = 1.5 Hz, 1 H) 7.37 (d, J = 8.8 Hz, 2 H) 4.57-4.68 (m, 1H) 4.45- 4.56 (m, 1 H) 4.15-4.29 (m, 1 H) 1.42 (d, J = 6.6 Hz, 3 H). A70

470.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.28 (s, 1H), 9.12 (s, 2H), 8.42 (d, J= 1.5 Hz, 1H), 8.40 (s, 1H), 7.89 (d, J = 1.5 Hz, 1H), 7.86- 7.82 (m,2H), 7.30 (d, J = 9.0 Hz, 2H), 3.06 (td, J = 3.5, 6.9 Hz, 1H), 1.18(tdd, J = 3.2, 6.3, 9.4 Hz, 1H), 1.02 (ddd, J = 3.7, 5.8, 9.6 A Hz, 1H),0.64 (d, J = 6.0 Hz, 3H), 0.39 (q, J = 6.2 Hz, 1H). 71

500.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 9.35 (s, 1H), 9.08 (s,2H), 8.52 (d, J = 1.6 Hz, 1H), 8.47 (s, 1H), 7.96 (s, 1H), 7.93 (s, 1H),7.83 (d, J = 1.6 Hz, 1H), 7.37 (d, J = 8.8 Hz, 2H), 4.02-3.96 (m, 1H),3.93 (d, J = 7.7 Hz, 1H), 3.65 (br s, 1H), 3.57- 3.51 (m, 2H), 1.64 (s,1H), 1.59-1.47 (m, 2H), 1.21 (br d, J = 6.6 Hz, 1H). A 72

416.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.35-9.27 (m, 3H), 9.08 (s, 1H), 8.45(d, J = 1.3 Hz, 1H), 8.25 (d, J = 1.3 Hz, 1H), 7.87 (d, J = 9.0 Hz, 2H),7.33 (d, J = 9.0 Hz, 2H). A 73

500.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.29 (s, 1H), 9.01 (s, 2H), 8.45 (d, J= 1.5 Hz, 1H), 8.38 (s, 1H), 7.86- 7.81 (m, 3H), 7.29 (d, J = 9.0 Hz,2H), 4.07 (dd, J = 3.1, 14.8 Hz, 1H), 3.94 (dd, J = 8.2, 14.8 Hz, 1H),3.82- 3.76 (m, 1H), 3.67-3.54 (m, 2H), 1.79-1.60 (m, 3H), 1.32-1.23 (m,1H). A 74

486.0 ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.35 (s, 1H), 9.09 (s,2H), 8.53 (s, 2H), 7.94 (d, J = 9.0 Hz, 2H), 7.83 (d, J = 1.3 Hz, 1H),7.37 (d, J = 8.8 Hz, 2H), 4.53 (br s, 1H), 4.08-3.93 (m, 2H), 3.54 (s,2H), 2.22-1.94 (m, 2H). A 75

486.0 ¹H NMR (400 MHz, DMSO-d₆) δ = 10.47 (s, 1H), 9.35 (s, 1H), 9.08(s, 2H), 8.56-8.46 (m, 2H), 7.97-7.91 (m, 2H), 7.81 (d, J = 1.5 Hz, 1H),7.36 (d, J = 8.8 Hz, 2H), 4.52 (br s, 1H), 4.03-3.95 (m, 2H), 3.68 (dt,J = 5.4, 8.8 Hz, 2H), 2.19-2.07 (m, 2H). A 76

500.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.25-9.42 (m, 1 H) 9.04 (s, 2 H) 8.48(d, J = 1.7 Hz, 1 H) 8.36 (s, 1 H) 7.77-7.94 (m, 3 H) 7.30 (d, J = 9.0Hz, 2 H) 4.50-4.56 (m, 1 H) 4.20-4.31 (m, 1 H) 3.71-3.81 (m, 1 H) 3.65(dd, J = 6.2, 4.4 Hz, 1 H) 2.54-2.67 (m, 1 H) 2.36- 2.49 (m, 1 H) 0.67(d, J = A 6.2 Hz, 3 H). 77

502.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.32 (s, 1H), 9.06 (s, 2H), 8.49 (s,1H), 8.47 (d, J = 1.5 Hz, 1H), 7.90-7.79 (m, 3H), 7.30 (d, J = 9.0 Hz,2H), 4.54-4.47 (m, 1H), 4.26-4.19 (m, 2H), 3.98 (dd, J = 6.5, 10.0 Hz,1H), 3.89 (dd, J = 6.0, 9.9 Hz, 1H), 3.76 (dd, J = 3.5, 9.7 Hz, 1H). A78

502.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.31 (s, 1H), 9.06 (s, 2H), 8.49 (s,1H), 8.47 (d, J = 1.8 Hz, 1H), 7.88-7.81 (m, 3H), 7.30 (d, J = 9.0 Hz,2H), 4.53-4.46 (m, 1H), 4.26-4.18 (m, 2H), 3.98 (dd, J = 6.6, 10.1 Hz,1H), 3.89 (dd, J = 5.7, 9.9 Hz, 1H), 3.76 (dd, J = 3.6, 9.8 Hz, 1H). A79

502.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.31 (s, 1H), 9.05 (s, 2H), 8.47 (d, J= 1.6 Hz, 1H), 8.39 (s, 1H), 7.88- 7.83 (m, 3H), 7.30 (d, J = 8.9 Hz,2H), 4.36 (br d, J = 5.1 Hz, 1H), 4.26 (br d, J = 9.0 Hz, 2H), 4.14 (dd,J = 5.2, 10.2 Hz, 1H), 4.04 (dd, J = 5.2, 10.7 Hz, 1H), 3.61 (dd, J =2.6, 10.2 Hz, 1H). A 80

444.0 ¹H NMR (400 MHz, MeOD-d₄) δ 8.33 (br d, J = 6.2 Hz, 2H), 7.95 (d,J = 1.3 Hz, 1H), 7.84 (br d, J = 9.0 Hz, 3H), 7.31-7.27 (m, 2H), 6.67(br s, 1H), 3.47 (br s, 1H), 0.78 (br s, 2H), 0.63 (br s, 2H). B 81

473.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 8.75-8.66 (m, 2H), 8.47(d, J = 1.3 Hz, 1H), 8.42 (s, 1H), 8.10 (br d, J = 9.0 Hz, 1H), 7.94 (d,J = 9.0 Hz, 2H), 7.84 (d, J = 1.3 Hz, 1H), 7.36 (br d, J = 8.8 Hz, 2H),3.24 (td, J = 3.4, 6.9 Hz, 1H), 0.75 (br s, 2H), 0.43 (br d, J = 6.4 Hz,2H). B 82

486.2 ¹H NMR (400 MHz, MeOD-d₄) δ 8.92 (s, 1H), 8.86 (s, 2H), 8.43 (d, J= 1.1 Hz, 1H), 7.99 (d, J = 1.1 Hz, 1H), 7.84 (d, J = 9.0 Hz, 2H), 7.30(d, J = 8.8 Hz, 2H), 4.11 (s, 3H), 3.39 (tt, J = 3.7, 7.0 Hz, 1H),1.01-0.92 (m, 2H), 0.77- 0.68 (m, 2H). B 83

506.2 ¹H NMR (400 MHz, CDCl₃-d) δ 9.42 (s, 1H), 8.90 (s, 2H), 8.40 (s,1H), 8.29 (s, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H),7.31 (br s, 2H), 4.42 (br s, 1H), 2.99-2.68 (m, B4H). B 84

486.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.35 (s, 1H), 9.13 (s, 1H), 9.04 (s,2H), 8.49 (d, J = 1.3 Hz, 1H), 7.98 (d, J = 1.3 Hz, 1H), 7.84 (d, J =9.0 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 4.78 (quin, J = 7.0 Hz, 1H),4.43-4.33 (m, 1H), 2.76- 2.60 (m, 2H), 2.07-1.93 (m, 2H). B 85

446.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.52 (br s, 1H), 8.38 (br s, 1H), 7.91(s, 1H), 7.84 (br d, J = 8.9 Hz, 3H), 7.29 (br d, J = 8.6 Hz, 2H), 6.65(br s, 1H), 4.79-4.66 (m, 1H), 1.39 (br d, J = 6.4 Hz, 6H). B 86

475.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 8.76 (d, J = 2.7 Hz,1H), 8.68 (d, J = 11.1 Hz, 2H), 8.51 (d, J = 1.5 Hz, 1H), 8.12 (br d, J= 9.8 Hz, 1H), 7.95 (d, J = 9.0 Hz, 2H), 7.77 (s, 1H), 7.37 (d, J = 9.0Hz, 2H), 4.12-4.03 (m, 1H), 1.32 (d, J = 6.7 Hz, 6H). B 87

484.2 ¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.61 (br s, 1H), 9.32(s, 1H), 9.09 (s, 2H), 8.56 (s, 1H), 7.99 (s, 1H), 7.91 (br d, J = 8.8Hz, 2H), 7.32 (br d, J = 8.6 Hz, 2H), 3.32 (br t, J = 7.4 Hz, 1H), 1.38(br s, 1H), 1.21 (br d, J = 6.6 Hz, 3H), 0.56 (br s, 1H), 0.41 (br s,1H), 0.20-0.12 (m, 1H), 0.01 (br d, J = 4.0 Hz, 1H). B 88

484.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.61 (br s, 1H), 9.32(s, 1H), 9.09 (s, 2H), 8.56 (s, 1H), 7.99 (s, 1H), 7.91 (br d, J = 8.8Hz, 2H), 7.32 (br d, J = 8.6 Hz, 2H), 3.32 (br t, J = 7.4 Hz, 1H), 1.38(br s, 1H), 1.21 (br d, J = 6.6 Hz, 3H), 0.56 (br s, 1H), 0.41 (br s,1H), 0.20-0.12 (m, 1H), 0.01 (br d, J = 4.0 Hz, 1H). B 89

488.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.82 (s, 2H), 8.60 (s, 1H), 8.44 (s,1H), 7.86 (d, J = 8.9 Hz, 2H), 7.80 (s, 1H), 7.32 (d, J = 8.8 Hz, 2H),4.37-4.28 (m, 1H), 4.14 (s, 3H), 1.45 (d, J = 6.6 Hz, 6H). B 90

462.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.52 (s, 1 H) 8.37 (s, 1 H) 7.90 (d, J= 1.8 Hz, 1 H) 7.79-7.88 (m, 3 H) 7.29 (d, J = 9.0 Hz, 2 H) 6.65 (d, J =2.0 Hz, 1 H) 4.71 (br s, 1 H) 3.57-3.75 (m, 2H) 1.44 (d, J = 6.8 Hz, 3H) B 91

472.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.31 (s, 1H), 8.99 (s, 2H), 8.56 (s,1H), 8.47 (d, J = 1.8 Hz, 1H), 7.85-7.80 (m, 2H), 7.72 (d, J = 2.0 Hz,1H), 7.29 (d, J = 9.0 Hz, 2H), 1.50 (s, 9H). B 92

480.0 ¹H NMR (400 MHz, CDCl₃-d) δ 9.31 (s, 1H), 8.80 (s, 2H), 8.34 (d, J= 1.5 Hz, 1H), 8.05-7.96 (m, 2H), 7.74 (d, J = 1.5 Hz, 1H), 7.67 (d, J =8.9 Hz, 2H), 7.22 (s, 1H), 5.82-5.44 (m, 1H), 4.16 (dt, J = 2.8, 14.7Hz, 2H). B 93

486.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.30 (s, 1 H) 9.05 (s, 2 H) 8.46 (s, 1H) 8.40 (s, 1 H) 7.76-7.93 (m, 3 H) 7.30 (d, J = 9.0 Hz, 2 H) 3.64-3.92(m, 1 H) 2.95 (br d, J = 4.0 Hz, 1 H) 1.30 (br s, 1 H) 1.08 (br s, 2 H)0.35 (br s, 1 H). B 94

470.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1 H) 9.33 (s, 1 H) 9.10 (s,2 H) 8.44-8.55 (m, 2 H) 7.94 (d, J = 9.0 Hz, 2 H) 7.80 (d, J = 1.5 Hz, 1H) 7.36 (d, J = 9.0 Hz, 2 H) 1.22 (s, 3 H) 1.14 (br s, 2 H) 0.53 (br s,2 H). B 95

462.1 ¹H NMR (400 MHz, CDCl₃-d)) δ 8.76 9.07 (br s, 1H), 7.93 (s, 1H),7.72-7.55 (m, 4H), 7.48 (s, 1H), 7.17 (br d, J = 8.7 Hz, 2H), 6.49 (s,1H), 4.56 (br s, 1H), 3.85 (br d, J = 12.0 Hz, 1H), 3.48 (br d, J = 8.6Hz, 1H), 1.44 (br d, J = 6.8 Hz, 3H). B 96

494.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.32 (s, 1H), 9.00 (br s, 2H), 8.60(s, 1H), 8.48 (d, J = 1.8 Hz, 1H), 7.85-7.84 (m, 1H), 7.84- 7.81 (m,2H), 7.29 (d, J = 9.3 Hz, 2H), 6.14-5.83 (m, 1H), 4.45-4.32 (m, 1H),1.66 (d, J = 7.1 Hz, 3H). B 97

463..1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.23 (s, 1H), 8.60 (s, 1H), 8.44 (d,J = 1.8 Hz, 1H), 8.08 (s, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.87- 7.82 (m,2H), 7.30 (d, J = 9.2 Hz, 2H), 4.42-4.34 (m, 1H), 1.45 (d, J = 6.6 Hz,6H). B 98

494.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.32 (s, 1H), 9.00 (br s, 2H), 8.59(d, J = 0.7 Hz, 1H), 8.48 (d, J = 1.5 Hz, 1H), 7.86-7.84 (m, 3H), 7.29(d, J = 9.0 Hz, 2H), 6.15-5.82 (m, 1H), 4.47-4.32 (m, 1H), 1.66 (d, J =7.1 Hz, 3H). B 99

474.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.31 (s, 1H), 9.03 (s, 2H), 8.45 (d, J= 1.5 Hz, 1H), 8.33 (s, 1H), 7.88- 7.80 (m, 3H), 7.29 (d, J = 8.8 Hz,2H), 3.93-3.81 (m, 2H), 3.59-3.51 (m, 1H), 0.83 (d, J = 6.4 Hz, 2H). B100

486.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.31 (s, 1 H) 9.08 (s, 2 H) 8.37-8.54(m, 2 H) 7.80-7.94 (m, 3 H) 7.30 (d, J = 9.0 Hz, 2 H) 4.55 (dd, J = 7.5,6.6 Hz, 2 H) 4.31 (d, J = 7.5 Hz, 2 H) 4.24 (t, J = 6.2 Hz, 2 H)3.00-3.11 (m, 1 H). B 101

474.1 ¹H NMR (400 MHz, MeOD-d₄) δ = 9.05 (s, 1H), 8.78 (s, 2H), 8.20 (d,J = 1.5 Hz, 1H), 8.08 (s, 1H), 7.62- 7.56 (m, 3H), 7.04 (br d, J = 8.8Hz, 2H), 3.65-3.58 (m, 2H), 3.33-3.25 (m, 1H), 0.57 (d, J = 6.4 Hz, 3H).B 102

483.1 ¹H NMR (400 MHz, MeOD-d₄) δ = 9.34 (s, 1H), 9.08 (br s, 2H), 8.69(s, 1H), 8.49 (d, J = 1.5 Hz, 1H), 7.87-7.82 (m, 3H), 7.30 (d, J = 8.8Hz, 2H), 4.47-4.38 (m, 1H), 3.06-2.87 (m, 2H), 1.64 (d, J = 6.8 Hz, 3H).B 103

483.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.34 (s, 1H), 9.07 (br s, 2H), 8.69(s, 1H), 8.48 (d, J = 1.5 Hz, 1H), 7.86-7.82 (m, 3H), 7.29 (d, J = 8.8Hz, 2H), 4.45-4.39 (m, 1H), 3.03-2.86 (m, 2H), 1.63 (d, J = 6.8 Hz, 3H).B 104

500.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.37 (s, 1 H) 9.12 (s, 2H) 8.35-8.61(m, 2 H) 7.82-7.90 (m, 3 H) 7.30 (d, J = 8.9 Hz, 2 H) 4.77 (t, J = 7.1Hz, 1 H) 4.56-4.63 (m, 1 H) 4.41 (dd, J = 9.8, 6.5 Hz, 1 H) 4.11 (dt, J= 15.3, 6.1 Hz, 2 H) 3.57 (br s, 1 H) 1.33 (d, J = 6.7 Hz, 3 H). B 105

482.0 ¹H NMR (400 MHz, MeOD-d₄) δ 8.54 (s, 1H), 8.40 (s, 1H), 7.98 (s,1H), 7.89 (br s, 1H), 7.85 (d, J = 8.9 Hz, 2H), 7.30 (d, J = 8.6 Hz,2H), 6.69 (s, 1H), 6.00 (s, 1H), 5.18 (br s, 1H), 1.65 (d, J = 7.2 Hz,3H). B 106

482.0 ¹H NMR (400 MHz, MeOD-d₄) δ 8.54 (s, 1H), 8.40 (brs, 1H), 7.98 (s,1H), 7.93-7.77 (m, 2H), 7.92- 7.74 (m, 1H), 7.30 (d, J = 9.0Hz, 2H),6.69 (br s, 1H), 6.00 (br d, J = 2.2 Hz, 1H), 6.12-5.90 (m, 1H), 5.19(br s, 1H), 1.65 (d, J = 7.1 Hz, 3H). B 107

472.2 ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 9.63 (s, 2H), 9.21 (s,1H), 8.24 (d, J = 10.4 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.38 (br d, J= 8.8 Hz, 2H), 3.91 (s, 3H), 3.45-3.37 (m, 1H), 1.36 (d, J = 6.6 Hz,6H). C 108

461.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 9.30 (s, 1H), 8.63-8.51(m, 2H), 8.20 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H), 7.38 (d, J= 8.8 Hz, 2H), 3.87 (s, 3H), 2.64 (s, 3H). C 109

432.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (br s, 1H), 7.99 (br s, 1H), 7.77(br d, J = 8.6 Hz, 2H), 7.63 (br s, 1H), 7.21 (br d, J = 8.4 Hz, 2H),7.00 (br s, 1H), 3.79 (br s, 3H), 2.65-2.52 (m, 3H). C 110

488.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.39 (s, 1 H) 9.33 (s, 1 H) 9.02 (s,2 H) 8.35 (d, J = 1.8 Hz, 1 H) 7.92 (d, J = 9.0 Hz, 2 H) 7.66 (d, J =1.5 Hz, 1 H) 7.36 (d, J = 8.8 Hz, 2 H) 4.95 (t, J = 5.3 Hz, 1 H)4.14-4.27 (m, 1 H) 3.66 (br s, 1 H) 3.41-3.56 (m, 1 H) 2.67 (s, 3H) 1.29(br d, J = 7.1 Hz, 3 H). D 111

508.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1 H) 9.37 (s, 1 H) 9.12 (s,2 H) 8.59 (d, J = 1.5 Hz, 1 H) 7.89-7.97 (m, 2H) 7.86 (d, J = 1.5 Hz, 1H) 7.43-7.73 (m, 1 H) 7.37 (d, J = 9.0 Hz, 2 H) 4.26-4.57 (m, 1 H) 1.36(d, J = 7.1 Hz, 6 H). D 112

470.1 ¹H NMR (400 MHz, DMSO-d₆) δ 9.28 (s, 1H), 9.12 (s, 2H), 8.33 (d,1.5 Hz, 1H), 7.93 (d, J = 9.0 Hz, 2H), 7.83 (d, J = 1.5 Hz, 1H), 7.36(d, J = 9.0 Hz, 2H), 3.30-3.24 (m, 1H), 2.75-2.60 (m, 3H), 0.63-0.55 (m,2H), 0.47- 0.39 (m, 2H). D 113

472.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1 H) 9.35 (s, 1 H) 9.07 (s,2 H) 8.36 (d, J = 1.5 Hz, 1 H) 7.92 (d, J = 9.3 Hz, 2 H) 7.69 (d, J =1.5 Hz, 1 H) 7.36 (d, J = 9.0 Hz, 2 H) 4.13-4.34 (m, 1 H) 2.70 (s, 3 H)1.34 (d, J = 1.1 Hz, 6 H). D 114

542.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.31 (s, 1 H) 9.03 (s, 2 H) 8.35 (s, 1H) 7.83 (br d, J = 8.9 Hz, 2 H) 7.73 (s, 1H) 7.29 (br d, J = 8.7 Hz, 2H) 4.45 (dt, J = 14.1, 6.9 Hz, 1 H) 4.10 (br dd, J = 11.5, 3.4 Hz, 2 H)3.64 (br t, J = 11.8 Hz, 2 H) 3.43 (br t, 11.5 Hz, 1 H) 2.13-2.32 (m, 2H) 1.91 (br d, J = 12.3 Hz, 2H) 1.48 (br d, J = 7.1 Hz, 6 H). D 115

496.1 ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (br s, 1H), 10.52 (s, 1H), 8.50(br s, 1H), 7.99-7.87 (m, 4H), 7.68-7.67 (m, 1H), 7.36 (d, J = 9.3 Hz,2H), 6.62 (d, J = 2.0 Hz, 1H), 4.89 (br s, 1H), 1.36 (d, J = 6.8 Hz,6H). D 116

470.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.30 (s, 1H), 9.05 (s,2H), 8.29 (d, J = 1.3 Hz, 1H), 7.90 (d, J = 9.3 Hz, 2H), 7.70 (d, J =1.3 Hz, 1H), 7.33 (d, J = 9.0 Hz, 2H), 3.48 (s, 3H), 2.27-2.19 (m, 1H),1.18-0.97 (m, 4H). E 117

488.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 9.34 (s, 1H), 9.08 (s,2H), 8.46 (d, J = 1.7 Hz, 1H), 7.94 (d, J = 9.2 Hz, 2H), 7.82 (d, J =1.6 Hz, 1H), 7.37 (d, J = 9.0 Hz, 2H), 3.70 (s, 3H), 1.69 (s, 6H). E 118

480.0 ¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (s, 1H), 9.34 (s, 1H), 9.12 (s,2H), 8.57 (s, 1H), 7.93 (dd, J = 3.9, 5.1 Hz, 3H), 7.66-7.33 (m, 3H),3.57 (s, 3H). E 119

484.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 9.32 (s, 1H), 9.07 (s,2H), 8.44 (d, J = 1.3 Hz, 1H). 7.95 (d, J = 9.2 Hz, 2H), 7.76 (d, J =1.5 Hz, 1H), 7.37 (d, J = 8.9 Hz, 2H), 3.88 (quin, J = 8.3 Hz, 1H), 3.30(s, 3H), 2.45 (br d, J = 8.9 Hz, 4H), 2.16-2.05 (m, 1H), 2.02-1.89 (m,1H). E 120

460.2 ¹H NMR (400 MHz, MeOD-d₄) δ 9.35 (s, 1H), 9.08 (s, 2H), 8.47 (s,1H), 8.05 (s, 1H), 7.85 (d, J = 9.0 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H),5.09 (s, 2H), 3.57 (s, 3H). F 121

474.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.34 (s, 1H), 9.07 (s, 2H), 8.46 (d, J= 1.3 Hz, 1H), 8.00 (d, J = 1.3 Hz, 1H), 7.85 (d, J = 9.0 Hz, 2H), 7.31(d, J = 8.8 Hz, 2H), 4.92 (s, 2H), 3.56 (d, J = 4.3 Hz, 6H). F 122

460.0 ¹H NMR (400 MHz, DMSO)-d₆) δ 13.14 (br s, 1H), 10.48 (s, 1H), 8.32(br s, 1H), 7.96 (s, 1H), 7.93 (s, 2H), 7.88 (s, 1H), 7.36 (d, J = 8.6Hz, 2H), 6.67 (br s, 1H), 5.02 (s, 2H), 4.04 (br s, 4H). G 123

486.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.30 (s, 1 H) 9.06 (s, 2 H) 8.37 (d, J= 1.3 Hz, 1H) 7.80-7.88 (m, 3 H) 7.29 (d, J = 9.0 Hz, 2 H) 4.98-5.20 (m,2 H) 3.95- 4.05 (m, 1H) 3.61-3.72 (m, 2 H) 1.26 (d, J = 6.1 Hz, 3 H). G124

486.0 ¹H NMR (400 MHz, CDCl₃-d) δ 9.37 (s, 1H), 8.91 (s, 2H), 8.28 (s,1H), 8.13 (s, 1H), 7.81-7.69 (m, 3H), 7.29 (s, 1H), 5.21 (d, J = 16.3Hz, 1H), 4.99 (d, J = 16.3 Hz, 1H), 3.99-3.89 (m, 1H), 3.63-3.54 (m,1H), 3.50-3.44 (m, 1H), 1.31 (d, J = 6.2 Hz, 3H). G 125

486.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.32 (s, 1H), 9.11 (s, 2H), 8.39 (d, J= 1.5 Hz, 1H), 7.87-7.82 (m, 3H), 7.30 (d, J = 9.0 Hz, 2H), 5.16-4.96(m, 2H), 4.19-4.11 (m, 2H), 3.95 (d, J = 11.2 Hz, 1H), 1.00 (d, J = 6.8Hz, 3H). G 126

486.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.32 (s, 1H), 9.11 (s, 2H), 8.39 (d, J= 1.6 Hz, 1H), 7.88-7.81 (m, 3H), 7.30 (d, J = 9.0 Hz, 2H), 5.19-4.97(m, 2H), 4.18-4.12 (m, 2H), 3.95 (d, J = 11.4 Hz, 1H), 1.00 (d, J = 6.8Hz, 3H). G 127

476.0 ¹H NMR (400 MHz, DMSO-d₆) δ 12.96 (br s, 1H), 10.17 (s, 1H), 8.13(br s, 1H), 7.97-7.83 (m, 3H), 7.71 (s, 1H), 7.31 (d, J = 9.0 Hz, 2H),6.53 (br s, 1H), 4.53 (br s, 1H), 4.18 (s, 3H), 1.31 (d, J = 6.8 Hz,6H). H 128

502.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.29 (s, 1H), 9.01 (s, 2H), 8.16 (d, J= 1.8 Hz, 1H), 7.85-7.80 (m, 2H), 7.65 (d, J = 1.8 Hz, 1H), 7.29 (d, J =9.0 Hz, 2H), 4.66 (q, J = 7.2 Hz, 2H), 4.06 (quin, J = 6.8 Hz, 1H), 1.54(t, J = 7.1 Hz, 3H), 1.40 (d, J = 6.8 Hz, 6H). H 129

499.0 ¹H NMR (400 MHz, CDCl₃-d) δ 9.39 (s, 1H), 8.90 (s, 2H), 8.45 (s,1H), 8.40 (d, J = 1.5 Hz, 1H), 8.10 (s, 1H), 7.83 (d, J = 1.5 Hz, 1H),7.80-7.74 (m, 2H), 7.29 (s, 2H), 6.03 (s, 1H), 4.69 (br t, J = 7.1 Hz,1H), 3.71-3.47 (m, 2H), 2.81-2.58 (m, 2H), 1.26 (s, 2H). J 130

494.0 ¹H NMR (400 MHz, MeOD-d₄) δ 8.41 (br s, 1H), 8.06 (d, J = 1.5 Hz,1H), 7.88-7.83 (m, 2H), 7.48- 7.18 (m, 4H), 6.72 (br s, 1H), 3.49 (td, J= 3.3, 7.2 Hz, 1H), 0.77 (br s, 2H), 0.66 (br d, J = 5.7 Hz, 2H). E 131

464.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.53 (s, 1H), 8.40 (s, 1H), 7.95 (s,1H), 7.89 (s, 1H), 7.87-7.83 (m, 2H), 7.30 (d, J = 9.0 Hz, 2H), 6.67 (d,J = 2.1 Hz, 1H), 5.23-5.05 (m, 1H), 4.58 (d, J = 4.2 Hz, 1H), 4.46 (d, J= 4.0 Hz, 1H), 1.53 (d, J = 7.0 Hz, 3H). E 132

526.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (s, 1H), 9.37 (s, 1H), 9.06 (brs, 2H), 8.60 (d, J = 1.1 Hz, 1H). 7.97-7.84 (m, 3H), 7.70- 7.50 (m, 1H),7.44-7.33 (m, 2H), 4.74-4.48 (m, 3H). 1.44 (br d, J = 6.0 Hz, 3H) E 133

474.0 ¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (br s, 1H), 10.48 (s, 1H), 8.31(s, 1H), 7.94 (br d, J = 9.0 Hz, 3H), 7.89 (d, J = 1.2 Hz, 1H), 7.36 (brd, J = 8.7 Hz, 2H), 6.70 (s, 1H), 5.13-4.91 (m, 3H), 4.14 (br dd, J =2.9, 11.9 Hz, 1H), 3.96 (br d, J = 11.9 Hz, 1H), 0.86 (br d, J = 6.5 Hz,3H). G 134

462.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.07 (s, 1H), 8.44 (d, J = 1.7 Hz,1H), 8.05 (d, J = 1.6 Hz, 1H), 7.90-7.83 (m, 2H), 7.42 (s, 1H), 7.32 (d,J = 9.2 Hz, 2H), 4.95-4.92 (m, 1H), 1.48 (d, J = 6.6 Hz, 6H). M 135

526.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.32 (s, 1H), 9.01 (br s, 2H), 8.53(d, J = 1.8 Hz, 1H), 7.90-7.81 (m, 3H), 7.45-7.16 (m, 3H), 4.83-4.67 (m,2H), 4.64- 4.43 (m, 1H), 1.50 (br d, 7.1 Hz, 3H). E 136

513.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.24 (s, 1H), 8.08 (s, 1H), 7.83 (d, J= 9.0 Hz, 2H), 7.30 (d, J = 9.0 Hz, 2H), 5.17-5.12 (m, 2H), 5.10-5.03(m, 4H), 4.20- 4.10 (m, 2H), 2.30-2.25 (m, 3H) G 137

464.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.56-8.50 (m, 1H), 8.43-8.35 (m, 1H),7.96-7.92 (m, 1H), 7.89- 7.80 (m, 3H), 7.34-7.26 (m, 2H), 6.70-6.63 (m,1H), 5.03-4.89 (m, 1H), 4.58 (d, J = 4.2 Hz, 1H), 4.46 (d, J = 4.0 Hz,1H), 1.52 (d, J = 7.1 Hz, 3H). E 138

514.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.48 (s, 1H), 8.00 (d, J = 1.7 Hz,1H), 7.92 (s, 1H), 7.89-7.83 (m, 2H), 7.45-7.15(m, 3H), 6.67 (d, J = 2.1Hz, 1H), 5.14 (br dd, J = 6.2, 12.8 Hz, 1H), 4.75-4.46 (m, 2H), 1.53 (brd, J = 6.7 Hz, 3H). E, K 139

460.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 8.68 (s, 1H), 8.54 (d,J = 1.6 Hz, 1H), 7.95 (d, J = 9.0 Hz, 2H), 7.83 (d, J = 1.5 Hz, 1H),7.64 (d, J = 1.8 Hz, 1H), 7.37 (br d, J = 8.9 Hz, 2H), 6.58 (d, J = 1.8Hz, 1H), 3.87 (td, J = 6.6, 13.2 Hz, 1H), 3.61 (s, 3H), 1.38 (br d, J =6.6 Hz, 3H), 1.30 (br d, J = 6.5 Hz, 3H). E 140

460.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1 H) 8.59 (s, 1H) 8.41 (d, J= 1.5 Hz, 1H) 7.95 (d, J = 9.0 Hz, 2 H) 7.89-7.81 (m, 2 H) 7.36 (d, J =8.8 Hz, 2 H) 6.59 (d, J = 2.0 Hz, 1 H) 4.90-4.71 (m, 1 H) 3.95 (s, 3 H)1.35 (d, J = 6.6 Hz, 6 H). E 141

474.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.16 (d, J = 1.7 Hz, 1H), 8.03 (d, J =1.7 Hz, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.88-7.82 (m, 2H), 7.32 (d, J =9.0 Hz, 2H), 6.77 (d, J = 2.3 Hz, 1H), 5.30-5.22 (m, 1H), 4.86- 4.81 (m,2H), 2.65 (dt, J = 6.3, 15.5 Hz, 1H), 2.15 (dd, J = 2.4, 15.1 Hz, 1H),1.08 (d, J = 6.6 Hz, 3H). N 142

486.1 ¹H NMR (400 MHz, CDCl₃-d) δ 9.35 (s, 1H), 8.93 (br s, 2H), 8.08(br s, 2H), 7.73 (br d, J = 9.0 Hz, 2H), 7.64 (s, 1H), 7.30-7.27 (m,2H), 4.56 (br d, J = 9.5 Hz, 2H), 4.22 (br s, 1H), 2.55 (br s, 1H), 1.90(br d, J = 14.1 Hz, 1H), 0.98 (d, J = 6.4 Hz, 3H). N 143

463.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.13 (s, 1 H) 8.74 (s, 1 H) 8.55 (s, 1H) 8.40 (d, J = 1.7 Hz, 1 H) 7.84 (d, J = 9.2 Hz, 2 H) 7.81 (d, J= 1.7Hz, 1 H) 7.29 (d, J = 9.0 Hz, 2 H) 4.33-4.16 (m, 1 H) 1.40 (d, J = 6.7Hz, 6 H) E, I 144

491.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.17 (s, 1 H) 8.79 (s, 1H) 8.32 (d, J= 1.7 Hz, 1H) 7.87-7.84 (m, 1 H) 7.83-7.80 (m, 2H) 7.29 (d, J = 9.0 Hz,2 H) 5.13-5.04 (m, 1H) 5.02-4.94 (m, 1 H) 4.27-4.18 (m, 1 H) 4.16- 4.07(m, 1 H) 3.95 (d, J = 12.1 Hz, 1 H) 1.02 (d, J = 6.5 Hz, 3 H) G, I 145

458.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.34 (dd, J = 5.0, 1.5 Hz, 1 H) 8.61(s, 1 H) 8.51 (d, J = 1.6 Hz, 1 H) 8.17 (dd, J = 8.4, 1.5 Hz, 1 H)8.00-7.94 (m, 2 H) 7.88-7.83 (m, 2 H) 7.31 (d, J = 9.0 Hz, 2H) 4.49-4.34(m, 1 H) 1.38 (d, 6.7 Hz, 6 H) M 146

475.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1 H) 8.39 (d, J = 1.6 Hz, 2H) 8.05-7.80 (m, 3 H) 7.37 (d, J = 9.0 Hz, 2 H) 5.13-4.94 (m, 2 H)4.94-4.82 (m, 1 H) 4.00 (s, 2 H) 0.87 (d, J = 6.5 Hz, 3 H). G, L 147

513.1 ¹H NMR (400 MHz, CDCl₃-d) δ 8.67 (s, 1H), 8.54 (s, 1H), 8.26 (d, J= 1.8 Hz, 1H), 7.91 (s, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.68- 7.61 (m,2H), 7.21 (s, 1H), 7.19-7.18 (m, 1H), 7.11- 6.78 (m, 1H), 4.51 (td, J =6.9, 14.0 Hz, 1H), 1.35 (d, J = 7.1 Hz, 6H). E 148

491.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 9.33 (d, J = 1.6 Hz,1H), 8.38 (s, 1H), 8.15 (d, J = 1.6 Hz, 1H), 8.01-7.89 (m, 3H), 7.36 (brd, J = 8.6 Hz, 2H), 5.10-4.92 (m, 2H), 4.86-4.78 (m, 1H), 4.18- 3.87 (m,2H), 0.84 (br d, J = 6.5 Hz, 3H) G 149

490.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.25 (s, 1H), 8.06 (s, 1H), 7.92 (d, J= 1.3 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 6.76(s, 1H), 5.39 (br d, J = 5.7 Hz, 1H), 3.66- 3.55 (m, 1H), 3.39 (br d, J= 12.7 Hz, 1H), 2.46 (br d, J = 3.5 Hz, 2H), 1.13 (d, J = 6.6 Hz, 3H). N150

502.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.30 (d, J = 1.1 Hz, 1H), 9.08 (br s,2H), 8.20 (s, 1H), 7.86-7.78 (m, 2H), 7.68 (s, 1H), 7.28 (br d, J = 8.2Hz, 2H), 4.36 (br s, 1H), 3.58-3.42 (m, 1H), 3.12 (br d, J = 13.5 Hz,1H), 2.49-2.35 (m, 1H), 2.33- 2.21 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H). N151

513.1 ¹H NMR (400 MHz, CDCl₃-d) δ 8.98 (br s, 1H), 8.34 (s, 1H), 7.96(br s, 1H), 7.89 (br s, 1H), 7.71 (br d, J = 7.1 Hz, 2H), 7.59 (br s,1H), 7.26 (s, 2H), 7.17-6.88 (m, 1H), 4.72-4.58 (m, 1H), 1.46-1.39 (m,1H), 1.44 (br d, J = 6.4 Hz, 6H) E, I 152

476.0 ¹H NMR (400 MHz, MeOD-d₄) δ 8.13 (s, 1H), 7.95 (s, 1H), 7.87-7.79(m, 3H), 7.33-7.26 (m, 2H), 6.75 (d, J = 2.2 Hz, 1H), 5.52-5.38 (m, 1H),4.33 (dd, J = 7.5, 11.2 Hz, 1H), 3.60-3.51 (m, 1H), 0.99- 0.93 (m, 3H).N 153

510.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.21-9.13 (m, 2H),8.75- 8.62 (m, 1H), 8.43 (d, J = 1.3 Hz, 1H), 7.97-7.90 (m, 2H), 7.80(s, 1H), 7.37 (d, J = 8.8 Hz, 2H), 5.12-4.90 (m, 2H), 4.14-3.95 (m, 2H),3.90 (d, J = 11.2 Hz, 1H), 0.83 (br d, J = 6.4 Hz, 3H). G 154

491.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.14 (s, 1 H) 8.78 (s, 1H) 8.08 (d, J= 1.5 Hz, 1 H) 7.91-7.77 (m, 2 H) 7.69 (d, J = 1.8 Hz, 1 H) 7.28 (d, J =9.3 Hz, 2 H) 4.67-4.53 (m, 2 H) 4.39 (td, J = 6.0, 2.3 Hz, 1 H) 2.63-2.44 (m, 1 H) 1.99-1.93 (m, 1 H) 1.00 (d, J = 6.4 Hz, 3 H) N 155

458.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.23 (s, 1H), 7.98 (s, 1H), 7.89-7.82(m, 3H), 7.30 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 2.0 Hz, 1H), 5.06 (br s,1H), 3.22- 2.91 (m, 3H), 2.36-2.26 (m, 1H), 0.86 (d, J = 6.6 Hz, 3H). G156

486.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.61 (s, 1H), 9.42 (d,J = 5.1 Hz, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.05 (dd, J = 2.3, 5.2 Hz,1H), 7.93 (d, J = 9.0 Hz, 2H), 7.84 (d, J = 1.5 Hz, 1H), 7.37 (d, J =9.0 Hz, 2H), 5.16-4.87 (m, 2H), 4.23-4.02 (m, 2H), 3.97-3.86 (m, 1H),0.79 (d, J = 6.6 Hz, 3H). G, I 157

491.1 ¹H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.32 (d, J = 1.5 Hz,1H), 8.17-8.08 (m, 2H), 7.93 (br d, J = 9.3 Hz, 2H), 7.78 (s, 1H), 7.35(br d, J = 8.3 Hz, 2H), 4.89 (br s, 1H), 4.60- 4.45 (m, 2H), 2.33 (br s,1H), 1.92 (br d, J = 12.2 Hz, 1H), 0.83 (br d, J = 6.4 Hz, 3H). N, I 158

510.2 ¹H NMR (400 MHz, MeOD-d₄) δ 9.12-9.03 (m, 2H), 8.52 (br s, 1H),8.11 (d, J = 1.7 Hz, 1H), 7.87-7.78 (m, 2H), 7.67 (d, J = 1.6 Hz, 1H),7.28 (d, J = 9.0 Hz, 2H), 4.70- 4.52 (m, 2H), 4.26 (br s, 1H), 2.65-2.45(m, 1H), 2.08-1.90 (m, 1H), 0.96 (d, J = 6.5 Hz, 3H) N 159

491.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.21 (s, 1 H) 8.36 (d, J = 1.6 Hz, 1H) 8.12 (s, 1H) 7.90 (d, J = 1.6 Hz, 1 H) 7.84 (d, J = 9.0 Hz, 2 H) 7.30(d, J = 8.9 Hz, 2 H) 5.14-5.08 (m, 1 H) 5.01 (s, 1 H) 4.45-4.34 (m, 1 H)4.13 (dd, J = 12.2, 2.9 Hz, 1 H) 3.97 (d, J = 12.1 Hz, 1 H) 1.12 (d, J =6.6 Hz, 3 H) G 160

475.2 ¹H NMR (400 MHz, MeOD-d₄) δ 9.09 (s, 1 H) 8.81 (s, 1H) 8.32 (d, J= 1.3 Hz, 1 H) 7.90-7.77 (m, 3 H) 7.30 (d, J = 8.9 Hz, 2 H) 5.09 (s, 1H) 5.00 (s, 1 H) 4.37 (br dd, J = 6.8, 2.1 Hz, 1 H) 4.14 (br dd, J =12.2, 2.8 Hz, 1 H) 4.01 (d, J = 12.0 Hz, 1 H) 1.16 (d, J = 6.6 Hz, 3 H)G 161

491.1 ¹H NMR (400 MHz, MeOD-d₄) δ = 8.42 (d, J = 1.5 Hz, 1H), 8.13 (d, J= 1.5 Hz, 1H), 8.05 (d, J = 3.4 Hz, 1H), 7.87 (s, 1H), 7.86-7.83 (m,2H), 7.31 (br d, J = 8.8 Hz, 2H), 5.23-5.20 (m, 1H), 5.15-4.99 (m, 2H),4.20 (dd, J = 3.2, 12.5 Hz, 1H), 4.02 (d, J = 12.2 Hz, 1H), 0.99 (d, J =6.4 Hz, 3H) G, M 162

505.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.33 (s, 1H), 7.96 (s, 1H), 7.85 (brd, J = 9.2 Hz, 2H), 7.72 (s, 1H), 7.31 (br d, J = 8.2 Hz, 2H), 5.13-5.00(m, 2H), 4.65-4.54 (m, 1H), 4.16 (br d, J = 9.9 Hz, 1H). 4.02-3.97 (m,1H), 2.82 (s, 3H), 1.04-0.99 (m, 3H). G 163

516.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.43 (s, 1H), 8.38 (d, J = 1.3 Hz,1H), 8.01 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 9.2 Hz, 2H), 7.31 (d, J =8.8 Hz, 2H), 5.14-4.97 (m, 2H), 4.80- 4.74 (m, 1H), 4.19 (dd, J = 3.1,12.3 Hz, 1H), 4.02 (d, J = 12.3 Hz, 1H), 1.03 (d, J = 6.6 Hz, 3H) G, M164

492.0 ¹H NMR (400 MHz, MeOD-d₄) δ 8.35 (d, J = 1.3 Hz, 1H), 7.97 (s,1H), 7.87- 7.80 (m, 3H), 7.29 (d, J = 8.8 Hz, 2H), 5.16-4.95 (m, 2H),4.76 (br s, 1H), 4.14 (dd, J = 3.2, 12.5 Hz, 1H), 4.00 (d, J = 12.1 Hz,1H), 1.09 (d, J = 6.4 Hz, 3H). G, M 165

492.0 ¹H NMR (400 MHz, MeOD-d₄) δ 8.17 (s, 1H), 7.98 (s, 1H), 7.87 (d, J= 4.6 Hz, 1H), 7.83 (d, J = 9.0 Hz, 2H), 7.30 (br d, J = 8.6 Hz, 2H),5.04 (br s, 1H), 4.80 (br d, J = 7.7 Hz, 2H), 2.61 (br d, J = 8.2 Hz,1H), 2.13 (br d, J = 14.8 Hz, 1H), 1.14 (d, J = 6.4 Hz, 3H). N, M 166

488.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.33 (s, 1H), 7.88-7.81 (m, 3H), 7.66(br s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 5.15-4.95 (m, 2H), 4.49 (br s,1H), 4.10 (dd, J = 2.9, 12.1Hz, 1H), 3.95 (d, J= 12.1 Hz, 1H), 2.10 (brs, 3H), 1.03 (br d, J = 6.4 Hz, 3H). G 167

486.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.33 (dd, J = 1.5, 4.9 Hz, 1H), 8.44(d, J = 1.6 Hz, 1H), 8.23 (dd, J = 1.5, 8.6 Hz, 1H), 8.03 (d, J = 1.6Hz, 1H), 7.97 (dd, J = 5.0, 8.6 Hz, 1H), 7.85 (d, J = 9.2 Hz, 2H), 7.30(d, J = 9.2 Hz, 2H), 5.07 (q, J = 16.1 Hz, 2H), 4.78 (br s, 1H),4.30-3.88 (m, 2H), 0.88 (d, J = 6.6 Hz, 3H). G, Q 168

502.1 ¹H NMR (400 MHz, CDCl₃-d) δ 9.37-9.31 (m, 1H), 9.04-8.84 (m, 2H),8.22 (d, J = 1.5 Hz, 1H), 8.12 (s, 1H), 7.76-7.71 (m, 2H), 7.29 (br s,1H), 7.27- 7.25 (m, 1H), 5.20-5.10 (m, 1H), 5.03-4.92 (m, 1H), 4.32 (d,J = 12.3 Hz, 1H), 4.05 (dd, J = 2.6, 12.5 Hz, 1H), 3.92 (br d, J = 3.5Hz, 1H), 3.67-3.57 (m, 1H), 3.43 (br d, J = 10.1 Hz, 1H). O 169

488.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.16-8.22 (m, 1H), 7.83 (d, J = 1.0Hz, 1H), 7.79-7.71 (m, 3H), 7.19 (d, J = 8.9 Hz, 2H), 6.61-6.56 (m, 1H),5.00- 4.84 (m, 2H), 4.64-4.43 (m, 1H), 4.11-4.05 (m, 1H), 4.00-3.91 (m,1H), 1.60- 1.44 (m, 1H), 1.22-1.02 (m, 1H), 0.48-0.39 (m, 3H) G 170

432.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.47-8.28 (m, 2H), 7.94 (s, 1H),7.90-7.77 (m, 3H), 7.37-7.20 (m, 2H), 6.73-6.54 (m, 1H), 4.38- 4.02 (m,2H), 1.10-0.98 (m, 3H). E 171

474.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.22 (s, 1H), 7.86-7.76 (m, 4H), 7.25(d, J = 9.3 Hz, 2H), 6.59 (d, J = 2.0 Hz, 1H), 5.34-5.25 (m, 1H), 4.33(br d, J = 4.9 Hz, 1H), 2.18-2.12 (m, 1H), 2.10-2.04 (m, 1H), 2.02- 1.90(m, 2H). P 172

474.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.16 (s, 1H), 7.77-7.72 (m, 2H), 7.71(br s, 1H), 7.19 (d, J = 9.3 Hz, 2H), 6.52 (d, J = 2.0 Hz, 1H),5.27-5.21 (m, 1H), 4.26 (br d, J = 4.9 Hz, 1H), 3.00 (dd, J = 4.9, 17.1Hz, 1H), 2.12-2.07 (m, 1H), 2.05-1.98 (m, 1H), 1.98- 1.91 (m, 2H) P 173

499.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.62-8.47 (m, 1H), 8.41 (s, 1H), 8.05(s, 1H), 7.85 (d, J = 9.0 Hz, 2H), 7.30 (d, J = 9.0 Hz, 2H), 5.21-4.94(m, 2H), 4.78-4.63 (m, 1H), 4.23- 3.93 (m, 2H), 1.05 (d, J = 6.6 Hz,3H). G, M 174

470.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.31 (s, 1H), 9.11 (s, 2H), 8.38 (d, J= 1.5 Hz, 1H), 7.89-7.79 (m, 3H), 7.29 (d, J = 8.4 Hz, 2H), 5.17-4.94(m, 2H), 4.21-4.09 (m, 2H), 3.95 (d, J = 11.5 Hz, 1H), 1.04-0.95 (m,3H). G 175

458.2 ¹H NMR (400 MHz, MeOD-d₄) δ 8.29 (s, 1H), 7.95 (s, 1H), 7.90-7.80(m, 3H), 7.29 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 2.0 Hz, 1H), 5.13-4.93(m, 3H), 4.16 (br dd, J = 3.0, 12.0 Hz, 1H), 3.98 (d, J = 12.1 Hz, 1H),1.00 (br d, J = 6.4 Hz, 3H). G 176

486.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.44 (d, J = 1.0 Hz, 1H), 9.27 (dd, J= 1.0, 5.3 Hz, 1H), 8.06 (d, J = 1.7 Hz, 1H), 7.91 (dd, J = 2.3, 5.3 Hz,1H), 7.76-7.69 (m, 2H), 7.62 (d, J = 1.7 Hz, 1H), 7.19 (d, J = 9.0 Hz,2H), 4.61-4.42 (m, 2H), 4.25 (dt, J = 3.0, 6.2 Hz, 1H), 2.58-2.39 (m,1H), 1.94-1.83 (m, 1H), 0.87- 0.78 (m, 3H). N, I 177

474.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.25 (s, 1H), 7.86-7.80 (m, 4H), 7.28(d, J = 8.7 Hz, 2H), 6.63 (d, J = 1.7 Hz, 1H), 4.25 (br t, J = 4.0 Hz,1H), 4.00 (br dd, J = 3.4, 13.0 Hz, 1H), 3.75 (br dd, J = 3.4, 13.2 Hz,1H), 3.28-3.22 (m, 1H), 3.17- 3.04 (m, 1H), 2.15-2.05 (m, 2H). P 178

502.1 ¹H NMR (400 MHz, CDCl₃-d) δ 9.22 (d, J = 5.1 Hz, 2H), 9.04 (s,1H), 8.14 (s, 1H), 7.75 (d, J = 9.0 Hz, 2H), 7.70 (d, J = 1.3 Hz, 2H),7.21 (d, J = 8.9 Hz, 2H), 5.08-5.00 (m, 1H), 4.89 (d, J = 16.3 Hz, 1H),4.30 (br d, J = 11.5 Hz, 1H), 4.05 (br d, J = 10.1 Hz, 2H), 3.56 (br dd,J = 7.1, 10.8 Hz, 1H), 3.47-3.36 (m, 1H). O, I 179

475.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.40 (dd, J = 2.0, 11.2 Hz, 2H), 8.16(s, 1H), 7.87-7.84 (m, 2H), 7.45 (d, J = 1.0 Hz, 1H), 7.30 (d, J = 9.3Hz, 2H), 5.67 (br dd, J = 2.0, 6.8 Hz, 1H), 5.14-4.98 (m, 2H), 4.23 (dd,J = 3.4, 12.2 Hz, 1H), 4.07 (d, J = 12.2 Hz, 1H), 1.16 (d, J = 6.4 Hz,3H). G, I 180

490.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.34 (br s, 1H), 7.90-7.79 (m, 4H),7.30 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 2.4 Hz, 1H), 5.30 (q, J = 6.4 Hz,1H), 4.76-4.76 (m, 1H), 4.77 (br s, 1H), 1.73 (d, J = 6.4 Hz, 3H), 1.46(dd, J = 7.1, 12.0 Hz, 6H). R 181

474.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.39-8.29 (m, 1H), 7.92-7.80 (m, 4H),7.29 (d, J = 9.2 Hz, 2H), 6.63 (s, 1H), 5.01 (dd, J = 4.3, 6.1 Hz, 1H),3.96-3.65 (m, 2H), 2.25-1.90 (m, 4H). P 182

499.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.40 (s, 1H), 7.94 (d, J = 1.3 Hz,1H), 7.85 (d, J = 9.0 Hz, 2H), 7.30 (d, J = 9.0 Hz, 2H), 7.22 (s, 1H),5.16-4.95 (m, 2H), 4.49-4.35 (m, 1H), 4.14 (dd, J = 2.8, 12.2 Hz, 1H),4.05-3.97 (m, 1H), 1.07 (d, J = 6.4 Hz, 3H). G, Q 183

474.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.25 (s, 1H), 7.87-7.78 (m, 4H), 7.32-7.25 (m, 2H), 6.63 (d, J = 2.0 Hz, 1H), 4.29-4.21 (m, 1H), 4.06-3.94 (m,1H), 3.81-3.70 (m, 1H), 3.29- 3.22 (m, 1H), 3.15-3.05 (m, 1H), 2.16-2.05(m, 2H). P 184

508.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.53 (dd, J = 1.2, 2.2 Hz, 1H), 9.42(dd, J = 1.2, 5.1 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.03 (dd, J = 2.4,5.4 Hz, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.89-7.84 (m, 2H), 7.51-7.36 (m,1H), 7.32 (d, J = 9.3 Hz, 2H), 4.49 (td, J = 7.2, 13.9 Hz, 1H),1.54-1.43 (m, 6H). D, I 185

486.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.22 (dd, J = 1.4, 5.0 Hz, 1H), 8.11(d, J = 1.3 Hz, 1H), 8.09 (d, J = 1.7 Hz, 1H), 7.86 (dd, J = 5.0, 8.6Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.76-7.71 (m, 2H), 7.19 (d, J = 9.0Hz, 2H), 4.79 (br d, J = 2.7 Hz, 1H), 4.60-4.40 (m, 2H), 2.55-2.39 (m,1H), 1.95- 1.79 (m, 1H), 0.76 (d, J = 6.6 Hz, 3H). N, Q 186

494.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.60-9.56 (m, 1H), 9.42 (dd, J = 1.2,5.1 Hz, 1H), 8.58 (d, J= 1.5 Hz, 1H), 8.06 (dd, J = 2.2, 5.1 Hz, 1H),7.97 (d, J = 1.5 Hz, 1H), 7.90-7.84 (m, 2H), 7.32 (d, J = 9.3 Hz, 2H),7.26-7.10 (m, 1H), 4.19 (q, J = 7.3 Hz, 2H), 0.99 (t, J = 7.1 Hz, 3H). I187

476.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.33 (s, 1H), 7.89 (s, 1H), 7.87-7.81(m, 3H), 7.30 (d, J = 8.6 Hz, 2H), 6.66 (s, 1H), 5.18 (q, J = 6.3 Hz,1H), 4.58-4.29 (m, 2H), 1.74 (d, J = 6.6 Hz, 3H), 0.96 (br t, J = 7.2Hz, 3H). R 188

476.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.33 (s, 1H), 7.89 (s, 1H), 7.87-7.81(m, 3H), 7.30 (d, J = 8.6 Hz, 2H), 6.66 (s, 1H), 5.18 (q, J = 6.3 Hz,1H), 4.58-4.29 (m, 2H), 1.74 (d, 6.6 Hz, 3H), 0.96 (br t, J = 7.2 Hz,3H). R 189

493.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.46 (s, 1H), 9.39 (d, J = 5.3 Hz,1H), 8.62 (s, 1H), 8.51 (d, J = 1.5 Hz, 1H), 7.96 (dd, J = 2.3, 5.2 Hz,1H), 7.87-7.82 (m, 2H), 7.30 (d, J = 9.0 Hz, 2H), 6.13-5.82 (m, 1H),4.39 (br s, 1H), 1.68 (d, J = 7.1 Hz, 3H) J 190

462.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.34 (s, 1H), 7.91 (d, J = 1.5 Hz,1H), 7.84 (br d, J = 9.0 Hz, 3H), 7.29 (d, J = 9.0 Hz, 2H), 6.66 (d, J =2.0 Hz, 1H), 4.89 (s, 2H), 4.37 (br d, J = 15.2 Hz, 2H), 0.99 (t, J =6.9 Hz, 3H) R 191

502.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.29 (dd, J = 1.3, 5.1 Hz, 1H), 8.42(d, J = 1.5 Hz, 1H), 8.19 (dd, J = 1.4, 8.5 Hz, 1H), 8.00 (d, J = 1.5Hz, 1H), 7.95 (dd, J = 5.1, 8.6 Hz, 1H), 7.85 (d, J = 9.0 Hz, 2H), 7.30(d, J = 8.8 Hz, 2H), 5.15-4.99 (m, 2H), 4.67 (br s, 1H), 4.28 (d, J =12.6 Hz, 1H), 4.12 (dd, J = 3.0, 12.5 Hz, 1H), 3.45 (dd, J = 8.3, 10.9 OHz, 1H), 3.20 (dd, J = 5.1, 10.8 Hz, 1H). 192

493.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.36-9.32 (m, 1H), 8.64 (s, 1H), 8.54(d, J = 1.5 Hz, 1H), 8.19 (dd, J = 1.5, 8.6 Hz, 1H), 8.06 (d, J = 1.5Hz, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.32 (d, J = 9.0 Hz, 2H), 6.16-5.88(m, 2H), 4.95 (br d, J = 7.5 Hz, 1H), 1.72 (d, J = 7.1 Hz, 3H) J, I 193

508.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.36 (dd, J = 1.5, 4.9 Hz, 1H), 8.56(d, J = 2.0 Hz, 1H), 8.16-8.12 (m, 1H), 8.01-7.95 (m, 2H), 7.87-7.83 (m,2H), 7.51- 7.22 (m, 3H), 4.50-4.41 (m, 1H), 1.43 (d, J = 7.3 Hz, 6H) J,I 194

490.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.36 (dd, J = 1.4, 5.0 Hz, 1H), 8.59(d, J = 1.5 Hz, 1H), 8.21 (dd, J = 1.5, 8.6 Hz, 1H), 8.10 (d, J = 1.5Hz, 1H), 7.99 (dd, J = 5.1, 8.6 Hz, 1H), 7.89-7.83 (m, 2H), 7.38-7.11(m, 3H), 4.40-4.32 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H). J, I 195

488.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.32 (s, 1H), 9.08 (s, 2H), 8.41 (d, J= 1.5 Hz, 1H), 7.91-7.76 (m, 3H), 7.30 (br d, J = 8.8 Hz, 2H), 5.19 (q,J = 6.4 Hz, 1H), 4.28-4.00 (m, 2H), 1.75 (d, J = 6.6 Hz, 3H), 0.96 (t, J= 7.2 Hz, 3H) R 196

488.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.34 (dd, J = 1.5, 5.0 Hz, 1H), 8.46(d, J = 1.7 Hz, 1H), 8.18 (dd, J = 1.6, 8.4 Hz, 1H), 8.00-7.93 (m, 2H),7.85 (d, J = 9.0 Hz, 2H), 7.30 (d, J = 9.0 Hz, 2H), 5.21 (q, J = 6.4 Hz,1H), 4.50-4.19 (m, 2H), 1.76 (d, J = 6.6 Hz, 3H), 0.85 (t, J = 7.1 Hz,3H) R, I 197

463.2 ¹H NMR (400 MHz, MeOD-d₄) δ 7.88-7.82 (m, 3H), 7.49 (d, J = 1.3Hz, 1H), 7.32 (d, J = 9.0 Hz, 2H), 5.07-4.93 (m, 3H), 4.29-4.22 (m, 3H),4.11- 4.05 (m, 1H), 3.79 (q, J = 6.9 Hz, 2H), 2.39 (q, J = 7.2 Hz, 2H),1.58 (d, J = 6.5 Hz, 3H) G 198

502.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.31 (s, 1H), 9.03 (s, 2H), 8.40 (d, J= 1.7 Hz, 1H), 7.88-7.80 (m, 2H), 7.75 (d, J = 1.7 Hz, 1H), 7.29 (d, J =9.0 Hz, 2H), 5.29 (q, J = 6.4 Hz, 1H), 4.59-4.44 (m, 1H), 1.75 (d, J =6.4 Hz, 3H), 1.46 (t, J = 7.2 Hz, 6H) R 199

502.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.34 (d, J = 3.7 Hz, 1H), 8.44 (s,1H), 8.16- 8.06 (m, 1H), 7.95 (dd, J = 5.1, 8.4 Hz, 1H), 7.89-7.80 (m,3H), 7.29 (d, J = 8.8 Hz, 2H), 5.30 (q, J = 6.1 Hz, 1H), 4.37 (br s,1H), 1.75 (d, J = 6.4 Hz, 3H), 1.44 (br t, J = 6.7 Hz, 6H) R, I 200

488.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.18 (s, 1H), 9.02 (s, 2H), 8.04 (d, J= 1.6 Hz, 1H), 7.79-7.70 (m, 3H), 7.20 (d, J = 9.0 Hz, 2H), 5.21 (t, J =8.5 Hz, 1H), 4.97 (dd, J = 3.1, 8.9 Hz, 1H), 4.56 (br dd, J = 3.2, 8.2Hz, 1H), 3.16 (dd, J = 2.9, 12.2 Hz, 1H), 2.79 (dd, J = 3.3, 12.1 Hz,1H) S 201

480.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.32 (br d, J = 4.9 Hz, 1H), 8.53 (s,1H), 8.43 (s, 1H), 8.22 (br d, J = 8.6 Hz, 1H), 8.14-8.07 (m, 1H), 7.97(br dd, J = 5.0, 8.5 Hz, 1H), 7.87 (br d, J = 8.8 Hz, 2H), 7.31 (br d, J= 8.4 Hz, 2H), 6.13-5.84 (m, 1H), 4.87-4.78 (m, 2H) J, I 202

486.1 ¹H NMR (400 MHz, CDCl₃-d) δ 9.34 (s, 1H), 8.89 (s, 2H), 8.29 (brs, 1H), 8.17 (br s, 1H), 7.72 (br d, J = 10.1 Hz, 3H), 7.23 (s, 2H),5.14 (br s, 1H), 3.63 (br dd, J = 7.2, 12.1 Hz, 2H), 2.35-2.19 (m, 2H),2.07 (br d, J = 9.4 Hz, 1H), 1.95 (br s, 1H) P 203

514.2 ¹H NMR (400 MHz, MeOD-d₄) δ 8.28 (s, 1H), 7.91 (br d, J = 1.3 Hz,1H), 7.84 (br d, J = 9.0 Hz, 2H), 7.30 (br d, J= 8.8 Hz, 2H), 6.33 (s,1H), 5.12-4.95 (m, 3H), 4.22-3.92 (m, 2H), 2.10-1.97 (m, 1H), 1.12- 0.97(m, 5H), 0.83 (br d, J = 2.4 Hz, 2H) J, Q 204

485.11 ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H), 9.37 (dd, J = 1.4, 5.0Hz, 1H), 8.40 (d, J = 1.3 Hz, 1H), 8.11 (dd, J = 1.5, 8.6 Hz, 1H),7.99-7.83 (m, 4H), 7.36 (br d, J = 8.8 Hz, 2H), 5.16 (br d, J = 2.8 Hz,1H), 4.10 (br d, J = 1.5 Hz, 1H), 3.89-3.77 (m, 1H), 3.45 (br dd, J =3.9, 12.6 Hz, 1H), 3.21-3.11 (m, T, I 1H), 3.10-2.99 (m, 1H), 2.05-1.90(m, 2H) 205

525.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.35 (br d, J = 4.2 Hz, 1H), 8.58 (s,1H), 8.14 (br d, J = 8.2 Hz, 1H), 8.06-7.94 (m, 2H), 7.85 (br d, J = 8.6Hz, 2H), 7.35- 7.28 (m, 3H), 4.77 (br s, 3H), 1.53 (br d, J = 5.5 Hz,3H) J, I 206

473.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.34 (d, J = 4.9 Hz, 1H), 8.63 (s,1H), 8.52 (d, J = 1.3 Hz, 1H), 8.16 (dd, J = 1.2, 8.6 Hz, 1H), 8.02-7.94(m, 2H), 7.87 (d, J = 9.0 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 4.46-4.30(m, 1H), 3.67- 3.61 (m, 2H), 1.47 (d, J = 7.0 Hz, 3H) J, I 207

488.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.25 (dd, J = 1.4, 5.0 Hz, 1H), 8.31(dd, J = 1.3, 8.6 Hz, 1H), 8.16 (dd, J = 1.7, 8.5 Hz, 2H), 7.92 (dd, J =5.0, 8.7 Hz, 1H), 7.85 (d, J = 9.3 Hz, 2H), 7.30 (d, J = 9.0 Hz, 2H),5.36-5.28 (m, 1H), 5.23 (dd, J = 2.9, 8.2 Hz, 1H). 5.09 (dd, J = 2.6,8.6 Hz, 1H), 3.36 (dd, J = 2.8, 12.2 S Hz, 1H), 2.99 (dd, J = 3.4, 12.0Hz, 1H). 208

486.2 ¹H NMR (400 MHz, MeOD-d₄) δ 9.30 (s, 1H), 9.04 (s, 1H), 8.34 (d, J= 1.5 Hz, 1H), 7.85 (d, J = 9.0 Hz, 2H), 7.79 (d, J = 1.5 Hz, 1H), 7.30(br d, J = 8.8 Hz, 2H), 4.39 (br d, J = 4.2 Hz, 1H), 3.96-3.84 (m, 1H),3.76-3.65 (m, 1H), 3.35 (br s, 1H), 3.13 (br dd, J = 5.0, 17.3 Hz, 1H),2.16-2.02 (m, 2H) T 209

486.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.29 (s, 1H). 9.08-9.01 (m, 1H), 9.04(s, 1H), 8.33 (d, J = 1.5 Hz, 1H), 7.84 (d, J = 9.0 Hz, 2H), 7.79 (d, J= 1.5 Hz, 1H), 7.30 (br d, J = 8.8 Hz, 2H), 4.38 (br d, J = 4.4 Hz, 1H),3.96-3.82 (m, 1H), 3.70 (td, J = 5.6, 11.5 Hz, 1H), 3.35 (br d, J = 4.2Hz, 1H), 3.12 (br dd, J = 5.0, 17.3 Hz, 1H), 2.17-2.01 (m, 2H) T 210

486.2 ¹H NMR (400 MHz, MeOD-d₄) δ 9.32 (dd, J = 1.2, 5.0 Hz, 1H), 8.38(d, J = 1.3 Hz, 1H), 8.14 (dd, J = 1.2, 8.5 Hz, 1H), 7.98-7.91 (m, 2H),7.85 (d, J = 9.0 Hz, 2H), 7.30 (br d, J = 8.8 Hz, 2H), 4.38 (br d, J =4.4 Hz, 1H), 3.99-3.89 (m, 1H), 3.84-3.75 (m, 1H), 3.39- 3.34 (m, 1H),3.14 (br dd, J = 5.0, 17.5 Hz, 1H), 2.15- 2.00 (m, 2H) T, I 211

486.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.36-9.26 (m, 1H), 8.37 (d, J = 1.3Hz, 1H), 8.13 (dd, J = 1.3, 8.6 Hz, 1H), 7.96-7.90 (m, 2H), 7.84 (d, J =9.0 Hz, 2H), 7.29 (br d, J = 9.0 Hz, 2H), 4.37 (br d, J = 4.4 Hz, 1H),3.98-3.86 (m, 1H), 3.85-3.73 (m, 1H), 3.39- 3.33 (m, 1H), 3.13 (br dd, J= 5.1, 17.2 Hz, 1H), 2.16- 1.97 (m, 2H) T, I 212

474.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.32 (br s, 1H), 8.25 (br d, J = 4.9Hz, 1H), 8.15 (br s, 1H), 7.94 (br d, J = 13.9 Hz, 1H), 7.90-7.80 (m,2H), 7.31 (br s, 2H), 4.27 (br d, J = 5.7 Hz, 3H), 3.91 (br d, J = 7.1Hz, 2H), 0.90 (br d, J = 6.6 Hz, 3H) H, I 213

462.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.12 (s, 1H), 7.91-7.75 (m, 4H), 7.29(d, J = 8.9 Hz, 2H), 6.64 (s, 1H), 4.24 (s, 3H), 4.09- 3.95 (m, 2H),0.94 (br t, J = 7.0 Hz, 3H) H 214

477.1 ¹H NMR (400 MHz, MeOD-d₄) δ = 9.05 (s, 1H), 8.77 (s, 1H), 8.34 (d,J = 1.8 Hz, 1H), 7.86-7.80 (m, 2H), 7.78 (d, J = 1.8 Hz, 1H), 7.29 (d, J= 9.0 Hz, 2H), 5.18 (q, J = 6.6 Hz, 1H), 4.39-4.16 (m, 2H), 1.74 (d, J =6.6 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H) R 215

475.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.98 (s, 1H), 8.72 (s, 1H), 8.24 (d, J= 1.5 Hz, 1H), 7.82 (d, J = 9.0 Hz, 2H), 7.75 (d, J = 1.5 Hz, 1H), 7.28(d, J = 9.0 Hz, 2H), 4.32 (br dd, J = 3.0, 5.4 Hz, 1H), 4.07 (dd, J =3.6, 12.5 Hz, 1H), 3.83 (dd, J = 3.9, 12.5 Hz, 1H), 3.26 (dd, J = 7.2,9.4 Hz, 1H), 3.15-3.04 (m, 1H), 2.19-2.07 (m, 2H) T 216

489.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.07 (s, 1H), 7.86-7.80 (m, 3H), 7.78(d, J = 1.5 Hz, 1H), 7.28 (d, J = 9.0 Hz, 2H), 6.65 (d, J = 2.2 Hz, 1H),4.94 (br s, 1H), 4.63 (d, J = 11.9 Hz, 1H), 4.47 (br d, J = 12.1 Hz,1H), 4.03 (s, 1H), 0.99 (br d, J = 6.7 Hz, 3H) U 217

502.2 ¹H NMR (400 MHz, MeOD-d₄) δ 9.30 (s, 1H), 9.02 (s, 2H), 7.84-7.72(m, 3H), 7.62 (s, 1H), 7.28 (br d, J = 8.8 Hz, 2H), 4.30- 4.18 (m, 1H),4.15-4.01 (m, 2H), 3.83-3.72 (m, 2H), 2.56-2.37 (m, 1H), 2.10- 1.92 (m,1H) V 218

474.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.30 (s, 1H), 9.04 (s, 2H), 8.19 (d, J= 1.5 Hz, 1H), 7.83 (br d, J = 9.3 Hz, 2H), 7.69 (d, J = 1.5 Hz, 1H),7.29 (br d, J = 8.8 Hz, 2H), 4.25 (s, 3H), 3.75 (q, J = 7.3 Hz, 2H),1.00-0.90 (m, 3H) H 219

474.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.06 (s, 1H), 8.79 (s, 1H), 8.07 (s,1H), 7.82 (br d, J = 8.9 Hz, 2H), 7.68 (s, 1H), 7.29 (br d, J = 8.6 Hz,2H), 4.70-4.47 (m, 3H), 2.55 (br s, 1H), 2.07- 1.96 (m, 1H), 1.15 (br d,J = 6.1 Hz, 3H) G 220

490.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.03 (br s, 2H), 7.86 (br d, J = 8.9Hz, 3H), 7.31 (br d, J = 8.7 Hz, 2H), 6.81 (br s, 1H), 5.31 (br d, J =4.8 Hz, 2H), 5.13 (br d, J = 5.7 Hz, 1H), 3.53-3.39 (m, 2H), 1.60 (br d,J = 6.1 Hz, 1H), 1.55-1.45 (m, 1H) V 221

503.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.28 (s, 1H), 9.02 (s, 2H), 8.18 (d, J= 1.7 Hz, 1H), 7.86-7.79 (m, 2H), 7.65 (d, J = 1.7 Hz, 1H), 7.29 (br d,J = 9.0 Hz, 2H), 4.25 (s, 3H), 4.09-3.93 (m, 2H), 3.53 (dd, J = 4.9,11.1 Hz, 1H), 2.02 (s, 1H), 1.32 (d, J = 7.0 Hz, 3H). H 222

488.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.37-9.29 (m, 1H), 8.35 (d, J = 1.5Hz, 1H), 8.11 (dd, J = 1.3, 8.6 Hz, 1H), 7.95 (dd, J = 5.0, 8.5 Hz, 1H),7.87-7.80 (m, 3H), 7.29 (br d, J = 9.0 Hz, 2H), 4.27 (br d, J = 7.1 Hz,1H), 3.81 (dd, J = 8.8, 11.7 Hz, 1H), 3.61 (br dd, J = 5.6, 11.8 Hz,1H), 2.79 (s, 3H), 1.44 (br d, 6.4 Hz, 3H) J, I 223

492.0 ¹H NMR (400 MHz, MeOD-d₄) δ 8.11 (br s, 1H), 7.82 (br d, J = 9.0Hz, 3H), 7.76 (s, 1H), 7.29 (br d, J = 8.8 Hz, 2H), 6.64 (br s, 1H),4.45 (br s, 1H), 4.23 (s, 3H), 3.91 (br s, 1H), 3.61 (br s, 1H), 1.33(d, J = 7.0 Hz, 3H). H 224

504.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.30 (dd, J = 1.5, 5.1 Hz, 1H), 8.22(d, J = 1.7 Hz, 1H), 8.11 (dd, J = 1.6, 8.4 Hz, 1H), 7.93 (dd, J = 5.0,8.4 Hz, 1H), 7.86-7.78 (m, 3H), 7.29 (d, J = 8.9 Hz, 2H), 4.25 (s, 3H),3.96-3.89 (m, 2H), 3.52 (br d, J = 5.9 Hz, 1H), 1.37 (d, J = 6.6 Hz,3H). H, I 225

476.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.07 (s, 1H), 7.87-7.79 (m, 4H), 7.29(br d, J = 8.6 Hz, 2H), 6.65 (s, 1H), 4.51 (q, J = 11.4 Hz, 2H), 4.30(br s, 1H), 4.12 (br s, 1H), 3.75 (br s, 1H) U 226

488.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.31 (d, J = 5.0 Hz, 1H), 8.22-8.15(m, 2H), 7.98-7.89 (m, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.6Hz, 2H), 4.63-4.57 (m, 1H), 4.54- 4.47 (m, 1H), 4.29 (br s, 1H), 4.18(dd, 3.8, 12.8 Hz, 1H), 3.55 (br d, J = 12.8 Hz, 1H) U 227

488.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.29 (s, 1H), 9.05 (s, 2H), 8.15 (d, J= 1.6 Hz, 1H), 7.83 (d, J= 9.0 Hz, 2H), 7.73 (d, J= 1.6 Hz, 1H), 7.29(br d, J= 9.0 Hz, 2H), 4.59-4.46 (m, 2H), 4.29 (br s, 1H), 4.06 (dd, J =3.5, 11.7 Hz, 1H), 3.51-3.46 (m, 1H) U 228

488.1 ¹H NMR (400 MHz, MeOD-d₄) δ 8.32 (br s, 1H), 7.91 (s, 1H), 7.84(br d, J = 8.9 Hz, 3H), 7.30 (d, J = 8.8 Hz, 2H), 6.69 (br s, 1H), 4.96(br dd, J = 6.4, 10.4 Hz, 2H), 2.39-2.18 (m, 2H), 2.11-1.89 (m, 2H),0.92 (br d, J = 5.9 Hz, 3H) W 229

507.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.35 (s, 1H), 9.06 (s,2H), 8.57 (s, 1H), 7.95-7.89 (m, J = 8.9 Hz, 2H), 7.84 (s, 1H),7.69-7.41 (m, 1H), 7.38 (br d, 8.8 Hz, 2H), 5.10 (t, J = 5.0 Hz, 1H),4.40-4.31 (m, 1H), 3.61- 3.44 (m, 2H), 1.37 (br d, J = 7.0 Hz, 3H) J 230

511.1 ¹H NMR (400 MHz, DMSO-d₆) δ 13.31-13.18 (m, 1H), 10.52 (s, 1H),8.48 (s, 1H), 7.99-7.88 (m, 4H), 7.56 (br t, J = 52.1 Hz, 1H), 7.36 (brd, J = 8.9 Hz, 2H), 6.62 (br s, 1H), 5.21-5.12 (m, 1H). 4.86 (br dd, J =5.2, 10.7 Hz, 1H), 3.59-3.54 (m, 2H), 1.39 (br d, J = 6.8 Hz, 3H) J 231

524.0 ¹H NMR (400 MHz, MeOD-d₄) δ 9.31 (s, 1H), 9.03 (s, 2H), 8.52 (s,1H), 7.85 (br d, J = 9.3 Hz, 3H), 7.54-7.26 (m, 3H), 4.53 (br d, J = 5.6Hz, 1H), 3.78- 3.70 (m, 1H), 3.66-3.59 (m, 1H), 1.45 (br d, J = 7.2 Hz,3H) J 232

500.1 ¹H NMR (400 MHz, MeOD-d₄) δ 9.31 (s, 1H), 9.10 (br s, 2H), 8.43(d, J = 1.5 Hz, 1H), 7.85 (dd, J = 3.7, 5.3 Hz, 3H), 7.30 (br d, J = 8.8Hz, 2H), 5.03 (br s, 1H), 4.32 (br t, J = 6.1 Hz, 1H), 2.79-2.57 (m,1H), 2.25 (br t, J = 14.3 Hz, 1H), 2.05 (br d, J = 11.7 Hz, 1H), 1.73(br d, J = 14.7 Hz, 1H), 0.86 (d, J = 6.6 Hz, 3H) W *Biological datareported in Table 2 for the compounds whose stereochemistry is noted asarbitrarily assigned in Table 1 can be associated with the appropriatecompound of Table 1 by reference to the corresponding ¹H NMR data. It isthus possible that the compound associated with a given ¹H NMR andbiological data set will have the same absolute stereochemistry or adifferent absolute stereochemistry from the compound whosestereochemistry is noted as arbitrarily assigned in Table 1.

Biological Examples

-   Biological Assays-   ABL1 Biochemical Kinase Assay

ABL1 WT protein (64-515aa) containing an N-terminal His tag was producedby co-expression with YopH in Sf9 insect cells. Cells were harvested bycentrifugation and resuspended in 50 mM Tris, 500 mM NaCl, 5 mM β-ME, pH8.2. Cells were lysed by sonication and clarified by centrifugation.ABL1 was purified by affinity chromatography using a HisTrap column witha wash step in 4% wash buffer (50 mM Tris, 500 mM NaCl, 500 mMimidazole, 5 mM β-ME, pH 8.2) and eluted in a linear gradient of thesame buffer. Fractions containing ABL1 were pooled, concentrated andfurther purified using an ion exchange column washed with 50 mM Tris, pH8.3 and eluted with a linear gradient of elution buffer (50 mM Tris, 1MNaCl, pH 8.3). Purified protein was stored at −80° C. in 50 mM Tris (pH8.2), 300 mM NaCl, 1 mM DTT and 20% glycerol.

The activity of the enzyme and compound inhibition was tested using anEZ reader microfluidic mobility shift assay (PerkinElmer, Waltham,Mass.). For inhibition studies, compounds were serially diluted in DMSO,using an 11-point 3-fold format, from a 1000 μM top compoundconcentration. 20 nL per well of serial diluted compounds weretransferred to Greiner polypropylene flat-bottom 384-well assay platesusing an acoustic transfer system (Echo 550). A 15 μL, reaction mixturecontaining fluorescent peptide, enzyme, buffer, co-factors and detergentwas added to each well and incubated at room temperature (RT) for 30minutes. 5 μL, per well of an ATP solution was then added and reactionswere carried out for 90 minutes before being quenched with 70 μL ofstopping buffer containing 500 mM EDTA. The reactions were read on an EZReader (PerkinElmer, Waltham, Mass.) using a mobility shift readout. Thefinal concentrations in each reaction were 1.5 μM FL-Peptide 2(PerkinElmer, Waltham, Mass.), 1 nM ABL1 WT (64-515 aa) enzyme, 50 mMHEPES (pH 7.5), 1 mM EGTA, 2 mM DTT, 0.05% BSA, 10 mM MgCl2, 0.01%Triton-X100 and 20 μM ATP. The final DMSO concentration was 0.1% and thefinal inhibitor concentration ranged from 1000 nM to 0.017 nM. Eachcompound was tested in duplicate and the inhibitor dose response curvesanalyzed using IC₅₀ regression curve fitting using GraphPad Prism.

ABL1 K562 Assay

Compound activity was tested using the Cell Titer Glo assay (CTG,Promega). K562 cells (Chronic Myeloid Leukemia) were maintained inIMDM+10% FBS. One day prior to testing compound activity, 800 K562 cellsper well were plated in culture medium at 16K cells/mL and incubatedovernight at 37° C., 5% CO₂. Compounds were serially diluted in IMDM+10%FBS, using a 9-point 3-fold format, from a 2000 nM top compoundconcentration. DMSO concentration was kept constant at 0.4%. 50 μL perwell of serial diluted compounds were transferred to the platescontaining K562 cells and incubated at 37° C., 5% CO₂ for 72 h (finalDMSO concentration of 0.2%). After 72 h plates and CTG reagent wereequilibrated to room temperature for 30 minutes before addition of 25 μLper well CTG reagent. Plates were shaken for 2 minutes and thenincubated at room temperature for 10 minutes. The reactions were read onan EnVision luminescence reader (PerkinElmer, Waltham, Mass.). Eachcompound was tested in duplicate and the inhibitor dose response curvesanalyzed using IC₅₀ regression curve fitting using GraphPad Prism.

The results are tabulated below in Table 2.

TABLE 2 Example Abl WT IC₅₀ (nM) Abl K562 CC₅₀ (nM) 1 ND 28.36 2 0.3711.64 3 1.07 55.29 4 0.27 15.11 5 0.38 8.91 6 0.63 30.27 7 0.33 14.11 8ND 9.27 9 0.33 8.89 10 0.63 29.25 11 0.16 8.73 12 0.38 14.85 13 0.7124.41 14 0.86 41.08 15 0.41 5.22 16 0.58 13.80 17 0.34 8.32 18 0.51 8.1919 1.02 60.18 20 0.50 59.12 21 0.64 95.95 22 0.31 11.21 23 0.72 48.25 240.40 40.23 25 20.69 1000.00 26 2.31 114.56 27 4.78 383.74 28 0.57 69.0529 0.62 31.34 30 0.80 52.02 31 0.66 30.96 32 0.37 9.23 33 0.60 19.36 340.74 12.60 35 0.32 6.11 36 4.20 352.61 37 0.54 20.45 38 0.63 17.67 391.11 28.77 40 0.48 6.76 41 281.23 >1000 42 0.56 14.41 43 0.38 9.15 440.65 60.78 45 0.41 53.21 46 0.67 39.85 47 3.17 277.52 48 1.30 35.28 49ND 6.55 50 0.27 9.93 51 0.26 9.37 52 0.37 10.46 53 0.54 14.02 54 0.516.70 55 ND 15.16 56 ND 14.75 57 ND 8.25 58 0.43 11.62 59 0.47 18.27 600.36 8.00 61 0.47 13.76 62 0.45 17.28 63 0.59 15.35 64 0.48 7.32 65 0.7741.05 66 0.56 16.83 67 0.61 25.94 68 1.21 59.15 69 0.49 8.33 70 0.398.65 71 0.78 46.84 72 0.79 54.13 73 0.83 42.01 74 0.32 7.04 75 0.4115.88 76 0.55 27.44 77 0.71 34.04 78 1.03 98.87 79 0.41 15.20 80 0.3110.72 81 0.40 7.28 82 0.52 13.67 83 0.40 19.48 84 0.57 13.48 85 0.528.61 86 0.51 6.76 87 0.44 12.53 88 0.62 16.36 89 0.61 21.73 90 0.32 8.6591 0.50 6.85 92 0.50 6.37 93 0.52 23.27 94 0.52 14.25 95 0.33 25.07 960.47 11.19 97 0.59 9.35 98 0.42 4.20 99 0.41 22.67 100 0.46 26.49 1010.63 22.29 102 0.61 33.13 103 0.46 16.88 104 0.71 22.39 105 0.86 30.61106 0.29 6.84 107 0.77 35.25 108 0.73 51.59 109 1.74 236.76 110 0.517.82 111 0.60 6.48 112 0.30 4.30 113 0.40 6.43 114 0.25 8.34 115 0.547.55 116 0.46 18.58 117 0.43 26.60 118 0.34 12.02 119 0.48 17.50 1200.48 23.09 121 ND 21.59 122 0.42 15.45 123 0.58 12.86 124 0.83 36.29 1251.35 106.48 126 0.25 1.32 127 0.36 8.94 128 0.48 15.39 129 1.07 145.79130 0.45 6.56 131 0.36 10.46 132 0.54 8.06 133 0.31 4.34 134 0.65 23.11135 0.36 4.22 136 ND 178.51 137 0.56 5.96 138 0.52 20.01 139 2.49 141.67140 1.26 61.82 141 0.34 5.22 142 0.30 2.25 143 0.36 15.50 144 0.35 3.38145 0.57 17.00 146 0.33 15.95 147 0.39 5.26 148 0.54 7.89 149 0.36 4.11150 0.36 1.85 151 0.77 13.71 152 0.56 8.21 153 0.28 1.94 154 0.43 6.88155 0.97 17.09 156 0.35 3.92 157 0.35 8.93 158 0.34 2.72 159 0.28 2.31160 0.52 10.62 161 0.55 17.54 162 0.73 15.22 163 0.63 20.80 164 0.819.75 165 0.38 4.94 166 0.45 6.60 167 2.51 22.71 168 0.33 2.24 169 0.535.12 170 0.49 9.79 171 ND 19.33 172 ND 40.17 173 0.76 38.92 174 0.477.40 175 0.46 11.74 176 0.51 14.07 177 0.62 22.15 178 0.70 28.10 1791.52 130.86 180 1.13 37.62 181 0.76 47.14 182 0.59 7.22 183 0.38 11.31184 0.59 22.35 185 0.31 8.00 186 0.45 14.96 187 0.33 4.17 188 0.48 11.42189 0.49 16.35 190 0.87 17.51 191 0.46 7.72 192 0.62 7.46 193 0.53 12.75194 0.57 10.40 195 0.54 3.41 196 0.44 14.93 197 2.37 149.53 198 0.477.06 199 0.47 15.92 200 0.48 15.32 201 0.49 16.03 202 0.66 13.36 2030.77 17.71 204 0.41 42.03 205 0.97 >1000 206 0.55 26.56 207 1.41 101.03208 0.37 10.84 209 0.45 18.55 210 0.51 36.62 211 0.55 56.46 212 0.7322.02 213 0.44 9.77 214 0.45 17.46 215 1.03 45.52 216 0.99 194.06 2170.56 23.54 218 0.34 6.53 219 0.93 23.67 220 2.55 170.95 221 0.28 6.71222 0.67 29.06 223 0.26 4.46 224 1.00 45.33 225 8.71 54.91 226 27.98192.62 227 9.67 38.88 228 ND 13.93 229 ND 36.82 230 ND 6.98 231 ND 13.52232 ND 1.32 ND = not determined

In Vivo Efficacy In KCL-22 Xenograft Model—Dual Agent Treatment

6-8 week old female nude mice are implanted subcutaneously with 2×10⁶KCL-22 cells in 50% matrigel (BD Biosciences) in the right dorsalaxillary region. Drug treatment is initiated when tumor volume reachedan average of 189 mm³ (about 9 days post tumor implantation). Compoundsprovided herein, in a phosphate-buffered saline solution are preparedweekly and dosed by oral gavage at about 25-35 mg/kg twice daily, andNilotinib solution is dosed at 75mg/kg twice daily. Animals receiveeither single agent alone or combination of both simultaneously. Tumorvolume is determined by twice weekly digital calipering and calculatedas Length×Width²/2. Animals treated with nilotinib alone can achievetumor regression after 4 week daily treatment, but tumors can relapse,e.g., to >500 mm³ thereafter. Animals with nilotinib resistant tumorsthen receive daily treatment of a compound provided herein, and aremonitored for tumor response.

What is claimed is:
 1. A compound of formula (I) or (Ia):

or a tautomer thereof, or a pharmaceutically acceptable salt of any ofthe foregoing, wherein: L is —NH—CO—, —CO—NH—, —NH—SO₂—, or —SO₂—NH—; R¹is optionally substituted C₆—C₁₀ aryl, optionally substituted 5-10membered heteroaryl, optionally substituted 4-10 membered heterocycle,C(O)NR⁶R⁷, S(O)₂NR⁶R⁷, NR⁶COR⁷, NR⁶SO₂R⁷, or C(O)OR⁶; R² is H,optionally substituted C₁—C₆ alkyl, optionally substituted C₃—C₈cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl,optionally substituted C₂—C₆ alkenyl, optionally substituted C₂—C₆alkynyl, optionally substituted C₆—C₁₀ aryl, or optionally substituted5-10 membered heteroaryl; R³ is H, optionally substituted C₁—C₆ alkyl,optionally substituted C₂—C₆ alkenyl, optionally substituted C₂—C₆alkynyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, OR⁶, or NR⁶R⁷; or R² and R³ together with the interveningatoms form optionally substituted C₃—C₈ cycloalkyl or optionallysubstituted 4-10 membered heterocycloalkyl; R⁴ is optionally substitutedC₁—C₆ alkyl, optionally substituted C₂—C₆ alkenyl, or optionallysubstituted C₂—C₆ alkynyl; X is O or S; Y is CH, C—(C₁—C₂ alkyl), C-haloor N; Z is CR⁵ or N; R⁵ is H or halogen; R⁶ is H, optionally substitutedC₁—C₆ alkyl, optionally substituted C₃—C₈ cycloalkyl, optionallysubstituted 4-10 membered heterocycloalkyl, optionally substitutedC₆—C₁₀ aryl, or optionally substituted 5-10 membered heteroaryl; and R⁷is H, optionally substituted C₁—C₆ alkyl, optionally substituted C₃—C₈cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl,optionally substituted C₆—C₁₀ aryl, or optionally substituted 5-10membered heteroaryl; or R⁶ and R⁷ together with the nitrogen to whichthey are attached form an optionally substituted 4-7 memberedheterocycle, provided that the compound is other than (i)1H-Benzimidazole-7-carboxylic acid,5-[[(4-methoxyphenyl)sulfonyl]amino]-1-methyl- or (ii)1H-Benzimidazole-7-carboxylic acid,5-[[(4-ethoxyphenyl)sulfonyl]amino]-1-methyl-.
 2. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein: R¹ is C₆—C₁₀aryl, 5-10 membered heteroaryl, or 4-10 membered heterocycle, each ofwhich is optionally substituted by 1-3 substituents selected from thegroup consisting of halogen, cyano, hydroxyl, C₁—C₆ alkoxy, C₁—C₆ alkyl,and C₃—C₆ cycloalkyl; R² is C₁—C₆ alkyl, C₃—Cs cycloalkyl, 4-10 memberedheterocycloalkyl, C₂—C₆ alkenyl, C₂—C₆ alkynyl, C₆—C₁₀ aryl, or 5-10membered heteroaryl, each of which is optionally substituted by 1-3substituents selected from the group consisting of halogen, hydroxyl,C₁—C₆ alkoxy, C₁—C₆ alkyl, C₃—C₆ cycloalkyl, 4- to 6-memberedheterocyclyl, cyano, oxo, —C(O)NH(C₁—C₆ alkyl), and —C(O)NH(C₃—C₆cycloalkyl); R³ is C₁—C₆ alkyl, C₂—C₆ alkenyl, C₂—C₆ alkynyl, C₃—C₆cycloalkyl, 4- to 6-membered heterocycloalkyl, C₆—C₁₀ aryl, or 5- to10-membered heteroaryl, each of which is optionally substituted by 1-3substituents selected from the group consisting of halogen, hydroxyl,and C₁—C₆ alkyl; or R² and R³ together with the intervening atoms formC₃—C₈ cycloalkyl or 4-10 membered heterocycloalkyl, each of which isoptionally substituted by 1-3 substituents selected from the groupconsisting of C₁—C₆ alkyl, hydroxyl, C₁—C₆ alkyl-OH, —C(O)(C₁—C₆ alkyl),and oxo; R⁴ is C₁—C₆ alkyl, C₂—C₆ alkenyl, or C₂—C₆ alkynyl, each ofwhich is optionally substituted by 1-3 halogens; R⁶ is C₁—C₆ alkyl,C₃—C₈ cycloalkyl, 4-10 membered heterocycloalkyl, C₆—C₁₀ aryl, or 5-10membered heteroaryl, each of which is optionally substituted by 1-3substituents selected from the group consisting of halogen, hydroxyl,and C₁—C₆ alkyl; and R⁷ is C₁—C₆ alkyl, C₃—C₈ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆—C₁₀ aryl, or 5-10 membered heteroaryl, each ofwhich is optionally substituted by 1-3 substituents selected from thegroup consisting of halogen, hydroxyl, and C₁—C₆ alkyl; or R⁶ and R⁷together with the nitrogen to which they are attached form 4-7 memberedheterocycle optionally substituted by 1-3 substituents selected from thegroup consisting of halogen, hydroxyl, and C₁—C₆ alkyl.
 3. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, which is offormula (IA-1):


4. The compound of claim 3, or a pharmaceutically acceptable saltthereof, wherein the compound is selected from formula (IIA)-(IIH):

wherein: R¹⁰ is an optionally substituted 5-6 membered heteroaryl; R²⁰is optionally substituted C₁—C₃ alkyl, optionally substituted C₃—C₄cycloalkyl, or optionally substituted 4-6 membered heterocycloalkyl; R³⁰is H, optionally substituted C₁—C₃ alkyl, optionally substituted C₃—C₄cycloalkyl, or optionally substituted 5-6 membered heterocycloalkyl; andRing A is optionally substituted 5-6 membered heterocycloalkyl.
 5. Thecompound of claim 4, or a pharmaceutically acceptable salt thereof,wherein: R¹⁰ is 5-6 membered heteroaryl optionally substituted by 1-3substituents selected from the group consisting of halogen, cyano,hydroxyl, C₁—C₆ alkoxy, C₁—C₆ alkyl, and C₃—C₆ cycloalkyl; R²⁰ is C₁—C₃alkyl, C₃—C₄ cycloalkyl, or 4-6 membered heterocycloalkyl, each of whichis optionally substituted by 1-3 substituents selected from the groupconsisting of halogen, hydroxyl, C₁—C₆ alkoxy, C₁—C₆ alkyl, C₃—C₆cycloalkyl, 4- to 6-membered heterocyclyl, cyano, oxo, —C(O)NH(C₁—C₆alkyl), and —C(O)NH(C₃—C₆ cycloalkyl); R³⁰ is C₁—C₃ alkyl, C₃—C₄cycloalkyl, or 5-6 membered heterocycloalkyl, each of which isoptionally substituted by 1-3 substituents selected from the groupconsisting of halogen, hydroxyl, and C₁—C₆ alkyl; Ring A is 5-6 memberedheterocycloalkyl optionally substituted by 1-3 substituents selectedfrom the group consisting of C₁—C₆ alkyl, hydroxyl, C₁—C₆ alkyl-OH,—C(O)(C₁—C₆ alkyl), and oxo.
 6. The compound of claim 3, or apharmaceutically acceptable salt thereof, wherein: X is O.
 7. Thecompound of claim 3, or a pharmaceutically acceptable salt thereof,wherein: R¹ is 5-10 membered heteroaryl or 4-10 membered heterocycle,each of which is optionally substituted by 1-3 substituents selectedfrom the group consisting of halogen, cyano, hydroxyl, C₁—C₆ alkoxy,C₁—C₆ alkyl, and C₃—C₆ cycloalkyl.
 8. The compound of claim 3, or apharmaceutically acceptable salt thereof, wherein: R¹ is—CONH(cyclopropyl), —CONH₂, —CONHMe,


9. The compound of claim 3, or a pharmaceutically acceptable saltthereof, wherein: R¹ is pyrimidinyl or pyrazolyl, each of which isoptionally substituted by 1-3 substituents selected from the groupconsisting of halogen, cyano, hydroxyl, C₁—C₆ alkoxy, C₁—C₆ alkyl, andC₃—C₆ cycloalkyl.
 10. The compound of claim 3, or a pharmaceuticallyacceptable salt thereof, wherein: R² is C₁—C₃ alkyl or C₃—C₄ cycloalkyl,each of which is optionally substituted by 1-3 substituents selectedfrom the group consisting of halogen, hydroxyl, C₁—C₆ alkoxy, C₁—C₆alkyl, C₃—C₆ cycloalkyl, 4- to 6-membered heterocyclyl, cyano, oxo,—C(O)NH(C₁—C₆ alkyl), and —C(O)NH(C₃—C₆ cycloalkyl).
 11. The compound ofclaim 3, or a pharmaceutically acceptable salt thereof, wherein: R² ismethyl, ethyl, isopropyl, tertiary butyl, cyclopropyl, cyclobutyl,cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl,


12. The compound of claim 3, or a pharmaceutically acceptable saltthereof, wherein: R³ is H, methyl, isopropyl, difluoromethyl,hydroxyethyl, cyclopropyl, cyclobutyl, —C(Me)₂OH, —CH(Me)OH,methoxymethyl, hydroxymethyl, methoxy, ethoxy, —CH₂CH₂OH, ortetrahydropyranyl.
 13. The compound of claim 3, or a pharmaceuticallyacceptable salt thereof, wherein R² and R³ together form:


14. The compound of claim 3, or a pharmaceutically acceptable saltthereof, wherein: R⁴ is C₁—C₃ alkyl optionally substituted with 1-3 halosubstituents.
 15. The compound of claim 3, or a pharmaceuticallyacceptable salt thereof, wherein: R⁴ is CF₃ or CF₂Cl.
 16. The compoundof claim 3, or a pharmaceutically acceptable salt thereof, wherein: R⁵is H.
 17. The compound of claim 3, or a pharmaceutically acceptable saltthereof, wherein: Y is CH.
 18. The compound of claim 3, or apharmaceutically acceptable salt thereof, which is of formula (Id) or(Ie):


19. A compound selected from Examples 1-232, or a pharmaceuticallyacceptable salt thereof.
 20. A composition comprising the compound ofclaim 3, or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient.
 21. A method of inhibitingtyrosine kinase enzymatic activity of a protein selected from the groupconsisting of Abelson protein (ABL1), Abelson-related protein (ABL2),and a chimeric protein BCR-ABL1, comprising contacting an effectiveamount of the compound of claim 3, or a pharmaceutically acceptable saltthereof.
 22. A method of treating a disease, wherein modulation ofBCR-ABL1 activity prevents, inhibits, or ameliorates the pathologyand/or symptomology of the disease, in a patient, comprisingadministering to the patient a therapeutically effective amount of thecompound of claim 3, or a pharmaceutically acceptable salt thereof. 23.A method of treating leukemia in a patient comprising administering tothe patient a therapeutically effective amount of the compound of claim3, or a pharmaceutically acceptable salt thereof, wherein the leukemiais chronic myeloid leukemia (CML), acute myeloid leukemia (AML), oracute lymphoblastic leukemia (ALL).
 24. The method of claim 23, whereinthe leukemia is CML or ALL, and the method further comprisesadministering a therapeutically effective amount of a compound selectedfrom the group consisting of imatinib, nilotinib, dasatinib, bosutinib,ponatinib and bafetinib.
 25. The method of claim 23, wherein the CML isresistant to standard-of-care treatment.
 26. The method of claim 25,wherein the CML is resistant to treatment with one or more of imatinib,nilotinib, and dasatinib.
 27. The method of claim 23, wherein the AML issecondary AML, which develops after myelodysplastic syndromes (MDS) ormyeloproliferative neo-plasms (MPN).